Comparative Effectiveness of In-Hospital Use of Recombinant
AHRQ%Systematic%Review%% Surveillance%Program%
" CER$#21:$Comparative"Effectiveness"of"In2Hospital" Use"of"Recombinant"Factor"VIIa"for"Off2Label" Indications"vs"Usual"Care" $ $ Original$Release$Date:$May"2010" Surveillance$Report:"February"2012""" Surveillance$Report:"August"2016" $ Summary$of$Key$Findings$from$Surveillance$ Report:$ •" Key$Question$1:"Conclusions"are"likely"current."" •" Key$Question$2:"Conclusions"are"likely"current."" •" Key$Question$3a:"Conclusions"are"likely"current."" •" Key$Question$3b:"Conclusions"are"likely"current."" •" Key$Question$4a:"Conclusions"are"likely"current."$ •" Key$Question$4b.i:"Conclusions"are"likely"current."$ •" Key$Question$4b.ii:$Conclusions"are"likely"current."$ •" Key$Question$4c:"Conclusions"are"likely"current."One"expert"noted" prostatectomy"is"now"associated"with"lower"morbidity"due"to"the"use" of"laparoscopic"and"robotic"technology,"which,"although"unrelated"to" conclusions"on"the"off2label"use"of"rFVIIa,"provides"important"context" of"how"the"morbidity"associated"with"this"surgical"procedure"has" changed"over"time.$$ " Signal$Assessment:"The"signal"for"this"report"is"weak"suggesting"that" the"conclusions"in"the"original"systematic"review"are$up$to$date.$$
i" Authors:$" Stephanie"Veazie" Karli"Kondo" Kara"Winchell"" " Conflict$of$Interest:$ None"of"the"investigators"has"any"affiliations"or"financial"involvement"that"conflicts"with" the"material"presented"in"this"report."" " Acknowledgements:$ The"authors"gratefully"acknowledge"the"following"individuals"for"their"contributions"to" this"project:"Rose"Relevo"for"conducting"searches."
ii" Reviewers$ " Richard"P."Dutton,"MD,"MBA" Professor" Department"of"Anesthesiology" University"of"Maryland"School"of"Medicine" Baltimore,"MD" " Maureane"Hoffman,"MD,"PhD" Professor" Department"of"Pathology" Duke"University"School"of"Medicine" Durham,"NC"" " " " " " " " " " " " " " " " " " " " " " " " " " " $ "
iii" Table$of$Contents$ Introduction"...... "1" Methods"...... "1" Prior"Surveillance"...... "1" Literature"Searches"...... "2" Study"Selection"...... "2" Expert"Opinion"...... "2" FDA,"Health"Canada,"and"MHRA"Warnings"...... "3" Check"for"Qualitative"Signals"...... "3" Signal"Assessment"for"Currency"of"the"Systematic"Review"...... "4" Results"...... "4" Prior"Surveillance"...... "4" Literature"Search"...... "5" FDA,"Health"Canada,"and"MHRA"Black"Box"Warnings"...... "5" Expert"Opinion"...... "5" Identifying"Qualitative"Signals"...... "6" Signal"Assessment"...... "7" References"...... "9" Appendices"...... "11" Appendix"A."Search"Strategy"...... "A21" Appendix"B."Inclusion"and"Exclusion"Criteria"from"Original"Systematic"Review"...... "B21" Appendix"C."Literature"Search"Results"...... "C21" Appendix"D."Questionnaire"Sent"to"Expert"Reviewers"...... "D21" Abstracts"from"Relevant"Literature/References"...... "D219" Appendix"E."Summary"Table"...... "E21" References"...... "E222" " $ $ $ "
iv" Introduction$$ The"purpose"of"the"surveillance"process"for"the"EPC"Program"is"to"determine"whether"the" conclusions"of"a"systematic"review"are"current."The"surveillance"process"examines"the" conclusions"to"the"key"questions"as"written,"and"does"not"evaluate"the"currency"of"the"original" scope"(i.e.,"key"questions,"included"interventions)."Approximately"25"systematic"reviews"are" selected"for"surveillance"annually"based"on"popularity,"use"in"obtaining"continuing"medical" education"certificates,"potential"impact"for"changing"the"field,"and"use"in"clinical"practice" guidelines." " Comparative"Effectiveness"Review"(CER)"#21"titled"Comparative+Effectiveness+of+In2Hospital+ Use+of+Recombinant+Factor+VIIa+for+Off2Label+Indications+vs+Usual+Care,"was"originally"released" in"May"2010.1"" " The"key"questions"for"the"original"systematic"review"are"as"follows:"" " Key$Question$1.$Indications,"Populations,"and"Characteristics"of"Comparative"Studies"of"Off2 Label"rFVIIa"Use?" " Key$Question$2."Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing" Intracranial"Hemorrhage" " Key$Question$3a."Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing" Massive"Bleeding"from"Trauma"(Body"Trauma)" " Key$Question$3b."Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing" Massive"Bleeding"from"Trauma"(Brain"Trauma)"i.e.,"Traumatic"Brain"Injury"[TBI])" " Key$Question$4a."Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing"Liver" Transplantation" " Key$Question$4b.i."Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing" Cardiac"Surgery"(Adult"Cardiac"Surgery)" " Key$Question$4b.ii."Use"of"rFVIIa"for"Selected"Indications"in"Patient"With/Undergoing"Cardiac" Surgery"(Pediatric"Cardiac"Surgery)" " Key$Question$4c."Use"of"rFVIIa"for"Selected"Indications"in"Patient"With/Undergoing" Prostatectomy" " Our"surveillance"assessment"began"in"December"2015."We"conducted"an"electronic"search"for" literature"published"since"the"end"date"of"the"most"recent"surveillance"report"search"date."After" completing"a"scan"of"this"literature"to"identify"evidence"potentially"related"to"the"key"questions"in" this"systematic"review,"we"contacted"experts"involved"in"the"original"systematic"review"to" request"their"opinions"as"to"whether"the"conclusions"had"changed." " Methods$$ $ Prior$Surveillance$$ "
1" A"surveillance"report"for"the"original"systematic"review"was"released"in"February"2012,"and" included"a"search"for"relevant"literature"published"from"20082Jan"2012"among"five"general" medical"journals"(Annals"of"Internal"Medicine,"BMJ,"JAMA,"Lancet,"and"New"England"Journal"of" Medicine)"and"five"specialty"journals"(Journal"of"Trauma"Injury,"Infection"and"Critical"Careg" NeurocriticalCareg"Annals"of"Thoracic"Surgeryg"Transplantationg"and"Stroke),"expert"opinion," and"a"search"of"U.S."Food"and"Drug"Administration"(FDA)"surveillance"alerts"received"from"the" Emergency"Care"Research"Institute"(ECRI)."The"findings"from"this"report"are"included"in"our" assessment."" $ Literature$Searches$$ " We"conducted"a"literature"search"of"Ovid"MEDLINE"covering"January"2012"to"December"2015" using"the"identical"search"strategy"used"for"the"original"review1"and"searching"for"studies" published"since"the"end"date"of"the"most"recent"surveillance"search." " The"literature"search"to"assess"the"currency"of"conclusions"was"conducted"among"a"selection"of" the"top"10"high"profile"general"medical"interest"journals"and"specialty"journals"searched"in"2012" surveillance"report"(Annals"of"Internal"Medicineg"Annals"of"Thoracic"Surgeryg"BMJg"JAMA," Journal"of"Trauma"Injury,"Infection"and"Critical"Careg"Lancetg"Neurocritical"Careg"New"England" Journal"of"Medicineg"Strokeg"Transplantation)."However,"because"the"search"yielded"fewer"than" 10"studies,"we"removed"the"journal"limitations."The"search"strategy"is"reported"in"Appendix"A."" $ Study$Selection$$ " We"used"the"same"inclusion"and"exclusion"criteria"as"the"original"systematic"review,"with"one" exception."The"original"review"included"an"evaluation"of"the"Premier"database"from"200022008" to"“document"the"complete"range"of"clinical"indications"where"rFVIIa"is"being"used"off2label," including"information"on"real2world"in2hospital"practice"patterns”"(p."9).1"In"lieu"of"conducting"an" updated"analysis"of"the"Premier"database,"we"expanded"the"inclusion"criteria"for"the"first" component"of"KQ12"describing"clinical"indications"of"off2label"rFVIIa"use2"to"include"non2 comparative"registry"studies"(see"Appendix"B"for"a"full"description"of"the"inclusion/exclusion" criteria)."" " One"investigator"reviewed"the"titles"and"abstracts"of"200"randomly"selected"articles"out"of"612" total"unique"articles"identified"in"the"PubMed"search"(Appendix"C)."We"included"systematic" reviews"and"meta2analyses,"whether"or"not"they"were"included"(as"a"study"design)"in"the" original"systematic"review."For"systematic"reviews"and"meta2analyses,"we"considered"findings" only"if"all"included"studies"met"criteria"that"a)"all"studies"were"not"included"or"excluded"from"the" original"systematic"review,"b)"all"studies"were"not"included"in"a"prior"surveillance"report"(if" applicable),"and"c)"all"studies"met"inclusion"criteria"for"the"original"systematic"review."Reviews" for"which"one"or"more"study"did"not"meet"our"criteria"were"used"to"identify"potentially"relevant" primary"research."Reviews"of"systematic"reviews"were"not"included." $ Expert$Opinion$$ " We"shared"the"conclusions"of"the"original"systematic"review"and"most"recent"surveillance" assessment,"findings"from"the"literature"analysis,"and"the"newly"identified"studies"with"11" experts"in"the"field"(8"original"peer"reviewers"and"3"technical"expert"panel"[TEP]"members)"to" request"their"assessment"of"the"currency"of"the"original"review"conclusions"and"their" recommendations"of"any"relevant"new"studies."Two"subject"matter"experts"responded"to"our"
2" request."See"Appendix"D"for"the"form"experts"were"asked"to"complete."Of"note,"one"registry" study2"was"not"included"in"the"form,"as"we"decided"to"include"registry"studies"for"Key"Question"1" after"submitting"information"to"experts.""" " FDA,$Health$Canada,$and$MHRA$Warnings$ " We"reviewed"results"from"a"search"of"FDA"MedWatch"black"box"warnings,"Health"Canada" surveillance"warnings,"and"Medicines"and"Healthcare"Products"Regulatory"Agency"(MHRA)" surveillance"warnings."The"search"was"conducted"by"the"Emergency"Care"Research"Institute" (ECRI)."" $ Check$for$Qualitative$Signals$$ " The"authors"of"the"original"systematic"review"conducted"qualitative"and"quantitative"synthesis"of" data"on"indications,"populations,"and"characteristics"of"comparative"studies"of"off2label"rFVIIa" use"(KQ1),"as"well"as"the"use"of"rVIIa"among"individuals"with"intracranial"hemorrhage"(KQ2)," body"trauma"(KQ3a),"or"traumatic"brain"injury"(KQ3b),"or"individuals"undergoing"liver" transplantation"(KQ4a),"adult"cardiac"surgery"(KQ4b.i),"pediatric"cardiac"surgery"(KQ4b.ii),"or" prostatectomy"(KQ4c)."We"compared"the"conclusions"of"the"included"abstracts"to"the" conclusions"of"the"original"systematic"review"and"2012"surveillance"report,"assessed"expert" input,"and"reviewed"FDA,"Health"Canada,"and"MHRA"alert"information"to"identify"qualitative" signals"about"the"currency"of"conclusions." " Compilation$of$Findings$and$Conclusions$$ $ For"this"assessment"we"constructed"a"summary"table"(Appendix"E)"that"includes"the"key" questions"and"conclusions"from"the"original"systematic"review,"findings"of"the"new"literature" search,"and"expert"assessments"pertaining"to"each"key"question."Because"we"did"not"find"any" FDA,"Health"Canada,"or"MHRA"warnings,"we"did"not"include"a"column"for"this"in"the"summary" table."We"categorized"the"currency"of"conclusions"using"a"32category"scheme:" " •" Original"conclusion"is"still"valid"and"this"portion"of"the"systematic"review"is"likely"current"" •" Original"conclusion"is"possibly"out"of"date"and"this"portion"of"the"systematic"review"may" not"be"current"" •" Original"conclusion"is"out"of"date."" " We"considered"the"following"factors"when"making"our"assessments:"" " •" If"we"found"no"new"evidence"or"only"confirmatory"evidence"and"all"responding"experts" assessed"the"systematic"review"conclusion"as"still"valid,"we"classified"the"systematic" review"conclusion"as"likely"current."" •" If"we"found"some"new"evidence"that"might"change"the"systematic"review"conclusion," and/or"a"minority"of"responding"experts"assessed"the"systematic"review"conclusion"as" having"new"evidence"that"might"change"the"conclusion,"then"we"classified"the" systematic"review"conclusion"may"not"be"current."" •" If"we"found"new"evidence"that"rendered"the"systematic"review"conclusion"out"of"date"or" no"longer"applicable,"we"classified"the"systematic"review"conclusion"as"out"of"date." Recognizing"that"our"literature"searches"were"limited,"we"reserved"this"category"only"for" situations"where"a"limited"search"would"produce"prima"facie"evidence"that"a"conclusion" was"out"of"date,"such"as"the"withdrawal"of"a"drug"or"surgical"device"from"the"market,"a"
3" black"box"warning"from"FDA,"etc."" " Signal$Assessment$for$Currency$of$the$Systematic$Review$ We"used"the"following"considerations"in"our"assessment"of"currency"of"the"systematic"review:" " •" Strong$signal:$A"report"is"considered"to"have"a"strong"signal"if"new"evidence"is" identified"that"clearly"renders"conclusions"from"the"original"systematic"review"out"of"date," such"as"the"addition"or"removal"of"a"drug"or"device"from"the"market"or"a"new"FDA"boxed" warning." •" Medium$signal:$A"report"is"considered"to"have"a"medium"signal"when"new"evidence"is" identified"which"may"change"the"conclusions"from"the"original"systematic"review."This" may"occur"when"abstract"review"and"expert"assessment"indicates"that"some" conclusions"from"the"original"systematic"review"may"not"be"current,"or"when"it"is"unclear" from"abstract"review"how"new"evidence"may"impact"the"findings"from"the"original" systematic"review." •" Weak$signal:$A"report"is"considered"to"have"a"weak"signal"if"no"new"evidence"is" identified"that"would"change"the"conclusions"from"the"original"systematic"review."This" may"occur"when"no"new"evidence"is"identified,"or"when"some"new"evidence"is"identified" but"it"is"clear"from"abstract"review"and"expert"assessment"that"the"new"evidence"is" unlikely"to"change"the"conclusions"of"the"original"systematic"review." " Results$$ $ Prior$Surveillance$$ " Prior"surveillance"of"the"topic"included"15"studies"and"consultation"with"two"subject"matter" experts."" " •" Key$Question$1:"The"populations,"characteristics"and"indications"of"the"identified" comparative"studies3212,18223"were"similar"to"the"studies"in"the"original"systematic"review." Conclusions"were"determined"to"not"be"applicable"for"the"purpose"of"assessing" currency."" •" Key$Question$2:"The"conclusion"of"increased"risk"of"arterial"TEs"with"high"and"medium" doses"of"rFVIIa"use"for"intracranial"hemorrhage"was"determined"to"be"possibly"out"of" date"due"to"a"meta2analysis3"indicating"no"difference"between"rFVIIa"and"no2rFVIIa" groups"in"risk"of"arterial"TEs."However,+it+is+our+assessment+that+the+original+conclusion+ is+likely+current,+because+the+four+relevant+studies+from+the+identified+meta2analysis3+had+ previously+been+included+in+the+original+systematic+review.+Two"additional"RCTs4,5"were" also"congruent"with"the"original"conclusions"on"arterial"TEs."All"other"conclusions"were" determined"to"be"likely"current."" •" Key$Question$3a:"The"conclusion"of"no"difference"in"mortality"between"rFVIIa"and"no2 rFVIIa"in"RCTs"and"slightly"decreased"risk"of"mortality"with"rFVIIa"in"observational" studies"for"body"trauma"were"determined"to"be"possibly"out"of"date"due"to"a"RCT6" indicating"higher"mortality"with"the"use"of"rFVIIa"in"a"regression"analysis,"and"an" observational"study7"indicating"lower"242hour"mortality"in"rFVIIa"vs"no"rFVIIa"use"among" individuals"receiving"≥"30"units"of"packed"red"blood"cells"(RBCs)."However,+it+is+our+ assessment+that+the+original+conclusion+is+likely+current,+as+the+RCT6+that+conducted+the+ regression+analysis+found+similar+mortality+rates+when+comparing+rFVIIa+to+no2rFVIIa+ groups,+two+other+identified+RCTs8,9+were+congruent+with+the+findings+from+the+RCTs+in+ the+original+systematic+review,+and+the+identified+observational+study7+was+congruent+
4" with+the+findings+from+the+observational+studies+in+the+original+systematic+review.+ Identified"studies"were"also"congruent"with"the"original"conclusions"on"the"risk"of"TEs" and"units"of"RBCs"transfused.6,7,9"All"other"conclusions"were"determined"to"be"likely" current."" •" Key$Question$3b:"The"conclusion"of"no"evidence"on"RBC"transfusion"requirements"in" rFVIIa"groups"for"traumatic"brain"injury"was"determined"to"be"possibly"out"of"date"due"to" an"observational"study10"indicating"reduced"RBC"transfusion"requirements"in"the"rFVIIa" group"compared"to"no2rFVIIa"group."However,+it+is+our+assessment+that+this+conclusion+ is+likely+current,+as+evidence+remains+insufficient+to+form+a+conclusion."Identified"studies" were"congruent"with"the"original"conclusions"on"mortality10"and"arterial"TEs.3,10"All"other" conclusions"were"determined"to"be"likely"current." •" Key$Question$4a:"The"conclusion"that"there"is"a"trend"towards"reduced"RBC" transfusion"requirements"with"rFVIIa"use"for"liver"transplantation"was"determined"to"be" possibly"out"of"date"due"to"a"meta2analysis11"indicating"no"significant"difference"between" rFVIIa"and"no2rFVIIa"groups."However,+it+is+our+assessment+that+the+original+conclusion+ is+likely+current,+because+the+studies+included+in+the+identified+meta2analysis+had+ previously+been+included+in+the+original+systematic+review."This"meta2analysis11"was" congruent"with"the"original"conclusions"for"mortality."All"other"conclusions"were" determined"to"be"likely"current." •" Key$Question$4bi:"Conclusions"were"determined"to"be"likely"current."Findings"from"one" meta2analysis3""were"congruent"with"the"original"conclusions"of"no"difference"between" rFVIIa"and"no"rFVIIa"on"TEs"for"adult"cardiac"surgery."In"addition,"one"observational" study12"that"reported"conclusions,"but"no"data,"on"operating"room"time"provided" evidence"where"there"was"previously"none."However,"evidence"remains"insufficient"to" form"a"conclusion." •" Key$Question$4bii:"Conclusions"were"determined"to"be"likely"current."Findings"from"one" observational"study"added"to"the"evidence"base"on"mortality,"TEs,"and"units"of"whole" blood/RBC"transfusions"for"pediatric"cardiac"surgery,"however"evidence"remains" insufficient"to"form"conclusions."" •" Key$Question$4c:"Conclusions"were"determined"to"be"likely"current."No"new"studies" were"identified"on"prostatectomy."" $ Literature$Search$$ " The"literature"search"identified"612"unique"titles"from"the"PubMed"search."We"examined"a" random"selection"of"200"of"the"612"articles"(see"Appendix"C)."Upon"abstract"review,"153"of"the" randomly"selected"studies"were"rejected"because"they"did"not"meet"the"original"systematic" review"inclusion"criteria"(see"Appendix"B)."The"remaining"7"studies2,5,13217"were"examined"for" potential"to"change"the"results"of"the"original"systematic"review." $ FDA,$Health$Canada,$and$MHRA$Black$Box$Warnings$$ " We"did"not"find"any"FDA"black"box"warnings,"Health"Canada"surveillance"warnings,"or"MHRA" surveillance"warnings"relevant"to"the"key"questions"in"this"systematic"review." $ Expert$Opinion$$ " We"shared"the"conclusions"of"the"original"review"with"11"experts"in"the"field"(8"original"peer" reviewers"and"3"TEP"members)"to"request"their"assessment"of"the"currency"of"report"
5" conclusions"and"their"recommendations"of"any"relevant"new"studies."Two"subject"matter" experts"responded."" " One"expert"felt"KQ"224c"conclusions"were"up"to"date,"while"the"other"expert"did"not"comment"on" the"currency"of"conclusions."One"expert"was"surprised"we"identified"no"studies"on"the"use"of" rFVIIa"in"obstetric"populationsg"however"the"original"systematic"review"included"three" retrospective"comparative"studies"on"rFVIIa"use"in"obstetrics/gynecology"for"KQ"1"(note:"these" studies"were"not"explicitly"described"on"the"expert"form."The"form"listed"the"indications"that" comprised"69%"of"the"identified"comparative"studies,"ie,"cardiac"surgery,"trauma,"intracranial" hemorrhage,"liver"transplantation,"and"prostatectomy)."This"expert"also"noted"that" prostatectomy"is"now"associated"with"lower"morbidity,"given"the"use"of"laparoscopic"and"robotic" technology."The"other"expert"identified"a"relevant"study"for"KQ"12."This"expert"also"identified"a" potentially"relevant"study18"for"KQ1,"however"we"excluded"it"because"it"examined"human"rather" than"recombinant"rFVIIa.""" " Identifying$Qualitative$Signals$$ " Appendix"E"shows"the"original"key"questions,"the"conclusions"of"the"original"systematic"review" and"the"most"recent"surveillance"report,"the"results"of"the"literature"search,"expert"opinion,"and" the"assessment"of"the"currency"of"the"systematic"review." " •" Key$Question$1:"Conclusions"are"likely"current."The"2012"surveillance"report"noted"the" populations,"characteristics,"and"indications"of"identified"studies,"which"were"similar"to" the"original"review,"but"did"not"assess"the"currency"of"conclusions."For"the"2016" surveillance"report,"the"populations"and"characteristics"of"the"identified"studies"were" similar"to"the"studies"identified"in"the"original"systematic"review."" •" Key$Question$2:"Conclusions"are"likely"current."The"2012"surveillance"report" determined"that"the"conclusion"of"increased"risk"of"arterial"thromboembolic"events"(TEs)" with"high"and"medium"doses"of"rFVIIa"for"intracranial"hemorrhage"was"possibly"out"of" date,"due"to"evidence"from"a"meta2analysis3"indicating"no"difference"between"rFVIIa"and" no2rFVIIa"on"risk"of"arterial"TEs."However,+it+is+our+assessment+that+the+original+ conclusion+is+likely+current,+because+the+relevant+studies+from+the+identified+meta2 analysis+had+previously+been+included+in+the+original+systematic+review.+Two"additional" RCTs4,5"(one"from"the"2012"surveillance"report"and"one"from"the"2016"surveillance" report)"are"congruent"with"the"original"review’s"conclusions.+" •" Key$Question$3a:"Conclusions"are"likely"current."In"the"2012"surveillance"report,"the" conclusion"of"no"difference"in"the"risk"of"mortality"between"rFVIIa"and"no2rFVIIa"groups" for"body"trauma"in"RCTs"and"lower"risk"of"mortality"with"rFVIIa"in"observational"studies" was"determined"to"be"possibly"out"of"date,"due"to"one"identified"RCT6"indicated"higher" mortality"with"the"use"of"rFVIIa"in"a"regression"analysis,"and"one"observational"study7" indicated"lower"242hour"mortality"for"rFVIIa"versus"no"rFVIIa"among"individuals"receiving" ≥"30"units"of"packed"red"blood"cells"(RBC)."However,+it+is+our+assessment+that+the+ original+conclusion+is+likely+current,+as+the+RCT6+that+conducted+the+regression+analysis+ found+similar+mortality+rates+when+comparing+rFVIIa+to+no2rFVIIa+groups,+and+the+ observational+study7+was+congruent+with+the+findings+from+observational+studies+in+the+ original+systematic+review.+Two"other"identified"RCTs8,9"were"congruent"with"the"findings" from"RCTs"in"the"original"systematic"review."Additional"studies"identified"in"the"2012" surveillance"report"were"congruent"with"the"original"conclusions"on"the"risk"of"TEs"and" units"of"RBCs"transfused.6,7,9"No"studies"were"identified"in"the"2016"surveillance"report.""
6" •" Key$Question$3b:"Conclusions"are"likely"current."The"conclusion"of"no"evidence"on" RBC"requirements"for"rFVIIa"use"for"traumatic"brain"injury"was"determined"to"be" possibly"out"of"date"due"to"an"observational"study18"identified"in"the"2012"surveillance" report"that"found"reduced"RBC"units"among"those"in"the"rFVIIa"group."However,+it+is+our+ assessment+that+this+conclusion+is+likely+current,+as+evidence+remains+insufficient+to+form+ a+conclusion."In"addition,"an"observational"study15"identified"in"the"2016"surveillance" report"found"no"difference"between"rFVIIa"and"no2rFVIIa"groups"on"length"of"ICU"stay" where"no"evidence"was"found"in"the"original"review."Evidence"remains"insufficient"to" form"a"conclusion."" •" Key$Question$4a:"Conclusions"are"likely"current."The"2012"surveillance"report" determined"that"the"conclusion"of"a"trend"towards"reduced"RBC"transfusion" requirements"for"liver"transplantation"with"rFVIIa"use"may"be"out"of"date"due"to"a"meta2 analysis11"that"reported"no"difference"in"RBC"usage"between"rFVIIa"and"no2rFVIIa." However,+it+is+our+assessment+that+the+original+conclusion+is+likely+current,+because+the+ studies+from+the+meta2analysis+had+previously+been+included+in+the+original+systematic+ review.+This"meta2analysis11"was"congruent"with"the"original"conclusions"for"mortality."In" addition,"while"the"original"systematic"review"only"reported"on"prophylactic"use"of"rFVIIa," the"2016"surveillance"report"identified"one"observational"study"indicating"that"the" intraoperative"use"of"rFVIIa"is"associated"with"worse"outcomes"in"mortality,"blood" product"usage,"and"ICU"length"of"stay"compared"to"prophylactic"use"or"no2rFVIIa." Although"this"study"does"not"change"the"currency"of"the"original"conclusions,"it" contributes"new"evidence"comparing"timing"of"rFVIIa"administration,"which"was"not" reported"in"the"original"systematic"review.""+ •" Key$Question$4b.i:"Conclusions"are"likely"current."Findings"from"one"meta2analysis3"" were"congruent"with"the"original"conclusions"of"no"difference"between"rFVIIa"and"no" rFVIIa"on"TEs"for"adult"cardiac"surgery."In"addition,"one"observational"study12"that" reported"conclusions,"but"no"data,"on"operating"room"time"provided"evidence"where" there"was"previously"none."However,"evidence"remains"insufficient"to"form"a"conclusion." No"studies"were"identified"in"the"2016"surveillance"report."" •" Key$Question$4b.ii:"Conclusions"are"likely"current."No"evidence"on"the"use"of"rFVIIa"on" mortality"in"pediatric"cardiac"surgery"was"identified"in"the"original"systematic"review," while"the"2012"and"2016"surveillance"reports"each"identified"one"observational"study8,14" indicating"no"difference"in"mortality"rates"between"rFVIIa"and"no2rFVIIa."Evidence" remains"insufficient"to"form"a"conclusion."Additionally,"while"there"was"insufficient" evidence"on"TEs"and"units"of"whole"blood/RBC"transfusions"in"the"original"systematic" review,"the"observational"studies8,14"identified"in"the"2012"and"2016"surveillance"reports" found"no"difference"between"rFVIIa"and"no2rFVIIa"on"either"outcome."Evidence"remains" insufficient"to"form"conclusions."" •" Key$Question$4c:"Conclusions"are"likely"current."No"new"studies"were"identified"in" either"the"2012"or"2016"surveillance"reports."One"expert"noted"prostatectomy"is"now" associated"with"lower"morbidity"due"to"the"use"of"laparoscopic"and"robotic"technology," which,"although"unrelated"to"conclusions"on"the"off2label"use"of"rFVIIa,"provides" important"context"of"how"morbidity"associated"with"this"surgical"procedure"has"changed" over"time.$$ " Signal$Assessment$$ " The"SRC"conclusions"based"on"the"results"of"the"prior"surveillance"assessment,"literature" published"since"the"original"report,"FDA,!Health"Canada,"and"MHRA"Warnings,"and"expert"
7" assessment"is"that:"" " •" Key$Question$1:"Conclusions"are"likely"current."" •" Key$Question$2:"Conclusions"are"likely"current."" •" Key$Question$3a:"Conclusions"are"likely"current."" •" Key$Question$3b:"Conclusions"are"likely"current."" •" Key$Question$4a:"Conclusions"are"likely"current."$ •" Key$Question$4b.i:"Conclusions"are"likely"current."$ •" Key$Question$4b.ii:$Conclusions"are"likely"current."$ •" Key$Question$4c:"Conclusions"are"likely"current."One"expert"noted"prostatectomy"is" now"associated"with"lower"morbidity"due"to"the"use"of"laparoscopic"and"robotic" technology,"which,"although"unrelated"to"conclusions"on"the"off2label"use"of"rFVIIa," provides"important"context"of"how"the"morbidity"associated"with"this"surgical"procedure" has"changed"over"time.$ $ The"signal"for"this"report"is"weak"suggesting"that"the"conclusions"in"the"original"systematic" review"are$up$to$date.$$ $ $
8" References$ " 1." Yank"V,"Tuohy"CV,"Logan"AC,"et"al."AHRQ"Comparative"Effectiveness"Reviews." Comparative+Effectiveness+of+In2Hospital+Use+of+Recombinant+Factor+VIIa+for+Off2Label+ Indications+vs.+Usual+Care."Rockville"(MD):"Agency"for"Healthcare"Research"and"Quality" (US)g"2010." 2." Zatta"A,"McQuilten"Z,"Kandane2Rathnayake"R,"et"al."The"Australian"and"New"Zealand" Haemostasis"Registry:"ten"years"of"data"on"off2licence"use"of"recombinant"activated"factor" VII."Blood+transfusion+=+Trasfusione+del+sangue.+Jan"2015g13(1):86299." 3." Levi"M,"Levy"JH,"Andersen"HF,"Truloff"D."Safety"of"recombinant"activated"factor"VII"in" randomized"clinical"trials."The+New+England+journal+of+medicine.+Nov"4"2010g363(19):17912 1800." 4." Diringer"MN,"Skolnick"BE,"Mayer"SA,"et"al."Thromboembolic"events"with"recombinant" activated"factor"VII"in"spontaneous"intracerebral"hemorrhage:"results"from"the"Factor"Seven" for"Acute"Hemorrhagic"Stroke"(FAST)"trial."StrokeP+a+journal+of+cerebral+circulation.+Jan" 2010g41(1):48253." 5." Imberti"R,"Pietrobono"L,"Klersy"C,"Gamba"G,"Iotti"G,"Cornara"G."Intraoperative"intravenous" administration"of"rFVIIa"and"hematoma"volume"after"early"surgery"for"spontaneous" intracerebral"hemorrhage:"a"randomized"prospective"phase"II"study."Minerva+ anestesiologica.+Feb"2012g78(2):1682175." 6." Wade"CE,"Eastridge"BJ,"Jones"JA,"et"al."Use"of"recombinant"factor"VIIa"in"US"military" casualties"for"a"five2year"period."The+Journal+of+trauma.+Aug"2010g69(2):3532359." 7." Morse"BC,"Dente"CJ,"Hodgman"EI,"et"al."The"effects"of"protocolized"use"of"recombinant" factor"VIIa"within"a"massive"transfusion"protocol"in"a"civilian"level"I"trauma"center."The+ American+surgeon.+Aug"2011g77(8):104321049." 8." Dutton"RP,"Parr"M,"Tortella"BJ,"et"al."Recombinant"activated"factor"VII"safety"in"trauma" patients:"results"from"the"CONTROL"trial."The+Journal+of+trauma.+Jul"2011g71(1):12219." 9." Hauser"CJ,"Boffard"K,"Dutton"R,"et"al."Results"of"the"CONTROL"trial:"efficacy"and"safety"of" recombinant"activated"Factor"VII"in"the"management"of"refractory"traumatic"hemorrhage." The+Journal+of+trauma.+Sep"2010g69(3):4892500." 10."Brown"CV,"Foulkrod"KH,"Lopez"D,"et"al."Recombinant"factor"VIIa"for"the"correction"of" coagulopathy"before"emergent"craniotomy"in"blunt"trauma"patients."The+Journal+of+trauma.+ Feb"2010g68(2):3482352." 11."Chavez2Tapia"NC,"Alfaro2Lara"R,"Tellez2Avila"F,"et"al."Prophylactic"activated"recombinant" factor"VII"in"liver"resection"and"liver"transplantation:"systematic"review"and"meta2analysis." PloS+one.+2011g6(7):e22581." 12."Uber"WE,"Toole"JM,"Stroud"MR,"et"al."Administration"of"recombinant"activated"factor"VII"in" the"intensive"care"unit"after"complex"cardiovascular"surgery:"clinical"and"economic" outcomes."The+Journal+of+thoracic+and+cardiovascular+surgery.+Jun"2011g141(6):14692 1477.e1462." 13."Bucklin"MH,"Acquisto"NM,"Nelson"C."The"effects"of"recombinant"activated"factor"VII"dose"on" the"incidence"of"thromboembolic"events"in"patients"with"coagulopathic"bleeding."Thrombosis+ research.+May"2014g133(5):7682771." 14."Martinez"Lopez"MC,"Alcaraz"Romero"AJ,"Martinez"Lopez"AB,"Fernandez2Llamazares"CM," Ramos"Navarro"C."[Risk"assessment"of"thrombotic"events"after"the"use"of"activated"factor" VII]."Anales+de+pediatria+(Barcelona,+Spain+:+2003).+Sep"2013g79(3):1772181." 15."Pei"BB,"Li"CY,"Lu"X,"et"al."[Role"of"small2dose"recombinant"human"coagulation"factor"VIIa" for"coagulopathy"in"patients"with"isolated"traumatic"brain"injury]."Zhonghua+yi+xue+za+zhi.+Jun" 18"2013g93(23):178021783."
9" 16."Scheffert"JL,"Taber"DJ,"Pilch"NA,"McGillicuddy"JW,"Baliga"PK,"Chavin"KD."Timing"of"factor" VIIa"in"liver"transplantation"impacts"cost"and"clinical"outcomes."Pharmacotherapy.+May" 2013g33(5):4832488." 17."Yuan"Q,"Wu"X,"Du"ZY,"et"al."Low2dose"recombinant"factor"VIIa"for"reversing"coagulopathy"in" patients"with"isolated"traumatic"brain"injury."Journal+of+critical+care.+Feb"2015g30(1):1162120." 18."McMullin"NR,"Wade"CE,"Holcomb"JB,"et"al."Prolonged"prothrombin"time"after"recombinant" activated"factor"VII"therapy"in"critically"bleeding"trauma"patients"is"associated"with"adverse" outcomes."The+Journal+of+trauma.+Jul"2010g69(1):60269." 19."Lavigne2Lissalde"G,"Aya,"AG.,"Mercier,"FJ.,"Roger2Christoph,"S.,"Chauleur,"C.,"Morau,"E.," Ducloy2Bouthors,"AS.,"Mignon,"A.,"Raucoules,"M.,"Bongain,"A.,"Boehlen,"F.,"de"Moerloose," P.,"Bouvet,"S.,Fabbro2Peray,"P.,"Gris,"JC."Recombinant"human"FVIIa"for"reducing"the"need" for"invasive"second2line"therapies"in"severe"refractory"postpartum"hemorrhage:"a" multicenter,"randomized,"open"controlled"trial."Journal+of+Thrombosis+&+Haemostasis.+ 2015g13(4):5202529." " "
10" Appendices$ $ Appendix$A:$$Search$Strategy$ $ Appendix$B:$Inclusion$and$Exclusion$Criteria$from$Original$Systematic$Review$ $ Appendix$C:$Literature$Search$Results$ $ Appendix$D:$$Questionnaire$Sent$to$Expert$Reviewers$ $ Appendix$E:$Summary$Table
11" Appendix$A.$Search$Strategy$ $ Factor$VIIa$–$Main$Search$ Database"Searched" Database:"Ovid"MEDLINE(R)"and"Ovid"OLDMEDLINE(R)"<1946"to" December"18,"2015" November"Week"3"2015>,"Ovid"MEDLINE(R)"In2Process"&"Other"Non2 Indexed"Citations"
A21" 3"""""(novoseven"or"eptacog*"or"Niastase"or"proconvertin"or""novo"2" seven").mp."(596)" 4"""""ec"3"4"21"21.rn."(2979)" 5"""""(((7a"or"viia)"adj5"(factor"or"rfactor))"or"(("factor"vii""or""factor"7""or" fvii"or"rfvii"or""factor""seven")"adj5"(active"or"activa"ted))).mp."(4765)" 6"""""1"or"2"or"3"or"4"or"5"(5391)" 7"""""exp"Intracranial"Hemorrhages/"(60446)" 8"""""exp"Brain/"(1052784)" 9"""""exp"Skull/"(171184)" 10"""""(intracranial"or"intracerebral"or""basal"ganglia""or"brain*"or" "posterior"fossa""or"cerebral"or"parenchymal"or"subdural"or" subarachnoid"or"pituitary"or"epidural).mp."(1666061)" 11"""""7"or"8"or"9"or"10"(2053439)" 12"""""6"and"11"(501)" 13"""""animals/"not"humans/"(4072764)" 14"""""12"not"13"(485)" Date"Limit" 15"""""limit"14"to"yr="2012"2Current""(87)" % No%journal%limits%used%as%results%from%date%limit%is%<100% "" Factor$VIIa$YLiver$Transplantation,$etc$ Database"Searched" Database:"Ovid"MEDLINE(R)"and"Ovid"OLDMEDLINE(R)"<1946"to" December"18,"2015" November"Week"3"2015>,"Ovid"MEDLINE(R)"In2Process"&"Other"Non2 Indexed"Citations"
A22" December"18,"2015" November"Week"3"2015>,"Ovid"MEDLINE(R)"In2Process"&"Other"Non2 Indexed"Citations"
A23" Appendix$B.$Inclusion$and$Exclusion$Criteria$from$Original$ Systematic$Review$ " Inclusion"criteria:"" Off2label"indications"included:""" •" KQ1:"All"indications" •" KQ224:"Intracranial"hemorrhage,"body"trauma,"traumatic"brain"injury,"liver" transplantation,"adult"cardiac"surgery,"pediatric"cardiac"surgery,"prostatectomy." Outcomes"included:"" •" All"indications:"transfusion"requirements,"mortality,"thromboembolic"events" •" Intracranial"hemorrhage:"relative"or"absolute"change"in"hematoma"volume,"functional" outcome"as"measured"by"the"modified"Rankin"Scale"(mRS)" •" Body"trauma:"Acute"respiratory"distress"syndrome"(ARDS)" •" Traumatic"brain"injury:"Relative"or"absolute"change"in"hematoma"volume" •" Liver"transplantation:"Operating"room"(OR)"time,"intensive"care"unit"(ICU)"length"of"stay" •" Adult"cardiac"surgery:"ICU"length"of"stay" •" Pediatric"cardiac"surgery:"Time"to"chest"closure"in"operating"room" Comparators"included"usual"care/standard"care."" Study"designs:"" •" Key"Question"1:"RCTs"and"comparative"observational"studies"were"included."In"the" original"systematic"review,"authors"conducted"an"examination"of"Perspective" Comparative"Database"of"Premier"from"200022008"to"review"trends"and"the"range"of" clinical"conditions"in"which"in2hospital,"off2label"rFVIIa"is"used,"to"examine"the"clinical" and"demographic"characteristics"of"cases,"and"to"evaluate"the"relevance"of"the" indications"selected"for"in2depth"effectiveness"review."For"the"2016"surveillance"report," we"included"registry"studies"as"a"means"of"capturing"similar"data"on"indications," populations,"and"characteristics"of"off2label"rFVIIa.""""" •" Key"Question"224:""RCTs"and"comparative"observational"studies"were"included"for"the" evaluation"of"effectiveness."Non2comparative"observational"studies"were"included"for"the" evaluation"of"harms."" " Exclusion"criteria:" •" Abstracts"only" •" Inappropriate"intervention"or"outcome,"such"as:"" •" Human"FVIIa"and"modified"forms"of"rFVIIa"that"are"still"under"development" •" Outcomes"such"as"metabolism"or"half2life"that"are"not"clinically"relevant" •" Studies"in"healthy"volunteers"directed"at"monitoring"parameters"such"as"INR"or" thromboelastin"time." •" In"vitro"studies" •" On2label"indications"of"rFVIIa"(hemophilia"A"or"B"with"inhibitors"and"congenital"factor"VII" deficiency)"or"those"that"are"substantially"similar"to"on2label"indications"(Glanzmann’s" thrombasthenia,"hemophilia"C,"von"Willebrand"disease,"Bernard2Soulier"syndrome," Hermansky2Pudlak"syndrome,"and"other"congenital"bleeding"disorders.)" "
B21" Appendix$C.$Literature$Search$Results$ $ The"literature"search"identified"612"unique"titles."Listed"below"are"the"200"randomly"selected" articles"we"examined"in"our"assessment"of"the"currency"of"conclusions"in"the"original"systematic" review." " 1." Abbonizio"F,"Giampaolo,"A.,"Coppola,"A.,"Italian"Association"of"Haemophilia"Centres," Arcieri,"R.,"Hassan,"HJ."Therapeutic"management"and"costs"of"severe"haemophilia"A" patients"with"inhibitors"in"Italy."Haemophilia.+2014g20(4):e2432250." 2." Aberg"M,"Eriksson,"O.,"Mokhtari,"D.,"Siegbahn,"A."Tissue"factor/factor"VIIa"induces"cell" survival"and"gene"transcription"by"transactivation"of"the"insulin2like"growth"factor"1" receptor."Thrombosis+&+Haemostasis.+2014g111(4):7482760." 3." Aberg"M,"Eriksson,"O.,"Siegbahn,"A."Tissue"Factor"Noncoagulant"Signaling:" Mechanisms"and"Implications"for"Cell"Migration"and"Apoptosis."Seminars+in+Thrombosis+ &+Hemostasis.+2015g41(7):6912699." 4." Agrawal"P,"Thakur,"Z.,"Kulharia,"M."Homology"modeling"and"structural"validation"of" tissue"factor"pathway"inhibitor."Bioinformation.+2013g9(16):8082812." 5." Aissaoui"H,"Prevost,"C.,"Boucharaba,"A.,"Sanhadji,"K.,"Bordet,"JC.,"Negrier,"C.," Boukerche,"H."MDA29/syntenin"is"essential"for"factor"VIIa2induced"signaling,"migration," and"metastasis"in"melanoma"cells."Journal+of+Biological+Chemistry.+2015g290(6):33332 3348." 6." Aissaoui"H,"Prevost,"C.,"Boucharaba,"A.,"Sanhadji,"K.,"Bordet,"JC.,"Negrier,"C.," Boukerche,"H."MDA29/Syntenin"is"essential"for"factor"VIIa2induced"signaling,"migration," and"metastasis"in"melanoma"cells."Journal+of+Biological+Chemistry.+2015g290(43):25847." 7." Alikhan"R,"Rayment"R,"Keeling"D,"et"al."The"acute"management"of"haemorrhage," surgery"and"overdose"in"patients"receiving"dabigatran."Emergency+Medicine+Journal.+ 2014g31(2):1632168." 8." Almomen"A,"Aleem"A,"Alshaik"M,"Hasanato"R."Intrapulmonary"rFVIIa"for"life"threatening" pulmonary"hemorrhage"in"a"case"of"relapsing"acute"lymphoblastic"leukemia"and"platelet" refractoriness."Platelets.+2014g25(6):4522454." 9." Arellano2Rodrigo"E,"Lopez2Vilchez,"I.,"Galan,"AM.,"Molina,"P.,"Reverter,"JC.,"Carne,"X.," Villalta,"J.,"Tassies,"D.,"Lozano,"M.,"Diaz2Ricart,"M.,"Escolar,"G."Coagulation"Factor" Concentrates"Fail"to"Restore"Alterations"in"Fibrin"Formation"Caused"by"Rivaroxaban"or" Dabigatran"in"Studies"With"Flowing"Blood"From"Treated"Healthy"Volunteers."Transfusion+ Medicine+Reviews.+2015g29(4):2422249." 10." Aron"J,"Gosselin,"R.,"Moll,"S.,"Arkin,"CF.,"Mantha,"S."Effects"of"recombinant"factor"VIIa" on"thrombin"generation"and"thromboelastography"in"a"patient"with"dabigatran2associated" intracranial"hemorrhage."Journal+of+Thrombosis+&+Thrombolysis.+2014g37(2):76279." 11." Atas"E,"Kesik,"V.,"Gursel,"O."Treatment"of"massive"gastrointestinal"bleeding"occurred" during"autologous"stem"cell"transplantation"with"recombinant"activated"factor"VII"and" octreotide."Journal+of+Cancer+Research+&+Therapeutics.+2015g11(3):667." 12." Augoustides"J."Breakthroughs"in"anticoagulation:"advent"of"the"oral"direct"factor"Xa" inhibitors."Journal+of+Cardiothoracic+&+Vascular+Anesthesia.+2012g26(4):7402745." 13." Augustsson"C,"Persson,"E."In"vitro"evidence"of"a"tissue"factor2independent"mode"of" action"of"recombinant"factor"VIIa"in"hemophilia."Blood.+2014g124(20):317223174." 14." Banov"L,"Pavanello,"M.,"Piattelli,"G.,"Disma,"N.,"Severino,"M.,"Dufour,"C.,"Molinari,"AC." Successful"urgent"neurosugery"management"with"rFVIIa"mega"doses"in"a"child"with" haemophilia"A"and"high"titre"inhibitor."Blood+Coagulation+&+Fibrinolysis.+2014g25(5):5182 521." 15." Barton"C,"Johnson,"NB.,"Case,"J.,"Warden,"B.,"Hughes,"D.,"Zimmerman,"J.,"Roberti,"G.,"
C21" McMillian,"WD.,"Schreiber,"M."Risk"of"thromboembolic"events"after"protocolized"warfarin" reversal"with"32factor"PCC"and"factor"VIIa."American+Journal+of+Emergency+Medicine.+ 2015g33(11):156221566." 16." Bartosh"N,"Tomlin,"T.,"Cable,"C.,"Halka,"K."Newly"diagnosed"congenital"factor"VII" deficiency"and"utilization"of"recombinant"activated"factor"VII"(NovoSeven)."Clinical+ Pharmacology.+2013g5:53258." 17." Baudo"F,"Collins,"P.,"Huth2Kuhne,"A.,"Levesque,"H.,"Marco,"P.,"Nemes,"L.,"Pellegrini,"F.," Tengborn,"L.,"Knoebl,"P.,"EACH2"registry"contributors."Management"of"bleeding"in" acquired"hemophilia"A:"results"from"the"European"Acquired"Haemophilia"(EACH2)" Registry."Blood.+2012g120(1):29246." 18." Ben2Hadj2Khalifa"S,"Lakhal,"B.,"Nsiri,"B.,"Mahjoub,"T.,"Almawi,"WY."Factor"VII"levels," R353Q"and"2323P0/10"Factor"VII"variants,"and"the"risk"of"acute"coronary"syndrome" among"Arab2African"Tunisians."Molecular+Biology+Reports.+2013g40(5):379323798." 19." Bensen2Kennedy"D."Bringing"new"therapy"options"to"the"hemophilia"community." Thrombosis+Research.+2013g131(Suppl"2):S15218." 20." Bladbjerg"E,"Henriksen,"JE.,"Akram,"S.,"Gram,"J."Effects"of"mealtime"insulin"aspart"and" bedtime"neutral"protamine"Hagedorn"insulin"on"postprandial"coagulation"and"fibrinolysis" in"patients"with"type"2"diabetes."Diabetes,+Obesity+&+Metabolism.+2012g14(5):4472453." 21." Blatny"J,"Mathew,"P.,"Monagle,"P.,"Ovesna,"P.,"Fiamoli,"V."Safety"and"efficacy"of" recombinant"activated"factor"VII"in"nonhemophilia"children"with"severe"or"life2threatening" bleeding:"a"report"from"the"SeveNBleeP"registry."Blood+Coagulation+&+Fibrinolysis.+ 2014g25(4):3262332." 22." Bolton"S,"Sutton,"JC.,"Anumula,"R.,"Bisacchi,"GS.,"Jacobson,"B.,"Slusarchyk,"WA.," Treuner,"UD.,"Wu,"SC.,"Zhao,"G.,"Pi,"Z.,"Sheriff,"S.,"Smirk,"RA.,"Bisaha,"S.,"Cheney,"DL.," Wei,"A.,"Schumacher,"WA.,"Hartl,"KS.,"Liu,"E.,"Zahler,"R.,"Seiler,"SM."Discovery"of" nonbenzamidine"factor"VIIa"inhibitors"using"a"biaryl"acid"scaffold."Bioorganic+&+Medicinal+ Chemistry+Letters.+2013g23(18):523925243." 23." Bonnet"M,"Basso,"O."Prohemostatic"interventions"in"obstetric"hemorrhage."Seminars+in+ Thrombosis+&+Hemostasis.+2012g38(3):2592264." 24." Branchini"A,"Baroni,"M.,"Pfeiffer,"C.,"Batorova,"A.,"Giansily2Blaizot,"M.,"Schved,"JF.," Mariani,"G.,"Bernardi,"F.,"Pinotti,"M."Coagulation"factor"VII"variants"resistant"to"inhibitory" antibodies."Thrombosis+&+Haemostasis.+2014g112(5):9722980." 25." Brogden"T,"Bunin,"J.,"Kwon,"H.,"Lundy,"J.,"McD"Johnston,"A.,"Bowley,"DM."Strategies"for" ventilation"in"acute,"severe"lung"injury"after"combat"trauma."Journal+of+the+Royal+Army+ Medical+Corps.+2015g161(1):14221." 26." Bucklin"M,"Acquisto,"NM.,"Nelson,"C."The"effects"of"recombinant"activated"factor"VII" dose"on"the"incidence"of"thromboembolic"events"in"patients"with"coagulopathic"bleeding." Thrombosis+Research.+2014g133(5):7682771." 27." Butenas"S."Tissue"factor"structure"and"function."Scientifica.+2012g2012:964862." 28." Caballo"C,"Escolar,"G.,"Diaz2Ricart,"M.,"Lopez2Vilchez,"I.,"Lozano,"M.,"Cid,"J.,"Pino,"M.," Beltran,"J.,"Basora,"M.,"Pereira,"A.,"Galan,"AM."Impact"of"experimental"haemodilution"on" platelet"function,"thrombin"generation"and"clot"firmness:"effects"of"different"coagulation" factor"concentrates."Blood+Transfusion.+2013g11(3):3912399." 29." Callum"J,"Rizoli,"S."Plasma"transfusion"for"patients"with"severe"hemorrhage:"what"is"the" evidence?"Transfusion.+2012g52(1):30S237S." 30." Campello"E,"Zabeo,"E.,"Radu,"CM.,"Spiezia,"L.,"Gavasso,"S.,"Fadin,"M.,"Woodhams,"B.," Vettor,"R.,"Simioni,"P."Hypercoagulability"in"overweight"and"obese"subjects"who"are" asymptomatic"for"thrombotic"events."Thrombosis+&+Haemostasis.+2015g113(1):85296." 31." Cao"H,"Tian,"Q.,"Huang,"Y.,"Ye,"S.,"Xin,"Y.,"Lin,"F.,"Li,"C."Biochemical"characterization"of" prothrombin"complex"concentrates"in"China."Biologicals.+2015g43(2):84291." 32." Carmo"E,"Oladapo,"AO.,"Rothschild,"C."Comparing"The"Cost2Effectiveness"of"Apcc"Vs"
C22" Rfviia"In"on2Demand"Treatment"of"Bleeds"In"Hemophilia"A"Patients"With"Inhibitors:"A" Brazilian"Public"Health"System"Perspective."Value+in+Health.+2015g18(7):A666." 33." Changlani"D,"Devendaran,"V.,"Murmu,"UC.,"Ganesan,"S.,"Varghese,"R.,"Kumar,"RS." Factor"VII"for"excessive"bleeding"following"congenital"heart"disease"surgery."Asian+ Cardiovascular+&+Thoracic+Annals.+2012g20(2):1202125." 34." Cho"A,"Khosla,"R."A"case"of"massive"airway"clotting"after"use"of"activated"factor"VII"for" massive"hemoptysis:"management"with"flexible"bronchoscopy"and"cryoadhesion." Journal+of+Bronchology+&+Interventional+Pulmonology.+2013g20(3):2762277." 35." Clevenger."B."M,"SV."Transfusion"and"coagulation"management"in"liver"transplantation." World+Journal+of+Gastroenterology.+2014g20(20):614626158." 36." Coppola"A,"Windyga,"J.,"Tufano,"A.,"Yeung,"C.,"Di"Minno,"MN."Treatment"for"preventing" bleeding"in"people"with"haemophilia"or"other"congenital"bleeding"disorders"undergoing" surgery."Cochrane+Database+of+Systematic+Reviews.+2015g2:CD009961." 37." Cristiani"A,"Vettore,"S.,"Sambado,"L.,"Bulfone,"A.,"Moro,"S.,"Girolami,"A."Conformational" Changes"of"Congenital"FVII"Variants"with"Defective"Binding"to"Tissue"Factor" ARG304GLN"(FVII"Padua),"ARG"304TRP"(FVII"Nagoya)"and"ARG79GLN"(FVII"Shinjo"or" Tondabayashi)."International+Journal+of+Biomedical+Science.+2013g9(4):1852193." 38." Delcourt"C,"Anderson,"C."Acute"intracerebral"haemorrhage:"grounds"for"optimism"in" management."Journal+of+Clinical+Neuroscience.+2012g19(12):162221626." 39." Dewhirst"E."Towards"evidence2based"emergency"medicine:"best"BETs"from"the" Manchester"Royal"Infirmary."BET"2:"is"recombinant"factor"VIIa"beneficial"in"the" management"of"acute"spontaneous"intracerebral"haemorrhage?"Emergency+Medicine+ Journal.+2013g30(4):3402341." 40." Ding"Q,"Shen,"Y.,"Yang,"L.,"Wang,"X.,"Rezaie,"AR."The"missense"Thr211Pro"mutation"in" the"factor"X"activation"peptide"of"a"bleeding"patient"causes"molecular"defect"in"the" clotting"cascade."Thrombosis+&+Haemostasis.+2013g110(1):53261." 41." Dirkmann"D,"Gorlinger,"K.,"Gisbertz,"C.,"Dusse,"F.,"Peters,"J."Factor"XIII"and"tranexamic" acid"but"not"recombinant"factor"VIIa"attenuate"tissue"plasminogen"activator2induced" hyperfibrinolysis"in"human"whole"blood."Anesthesia+&+Analgesia.+2012g114(6):11822 1188." 42." Doshi"B,"Gangadharan,"B.,"Doering,"CB.,"Meeks,"SL."Potentiation"of"thrombin" generation"in"hemophilia"A"plasma"by"coagulation"factor"VIII"and"characterization"of" antibody2specific"inhibition."PLoS+ONE+[Electronic+Resource].+.+2012g7(10):e48172." 43." Eggers"K,"Kempf,"T.,"Lind,"L.,"Sundstrom,"J.,"Wallentin,"L.,"Wollert,"KC.,"Siegbahn,"A." Relations"of"growth2differentiation"factor215"to"biomarkers"reflecting"vascular"pathologies" in"a"population2based"sample"of"elderly"subjects."Scandinavian+Journal+of+Clinical+&+ Laboratory+Investigation.+2012g72(1):45251." 44." Elizalde"M,"Slobodskoy,"L.,"Diodato,"M.,"Chang,"J.,"Chedrawy,"EG."Use"of"recombinant" factor"VII"in"cardiac"surgery."Recent+Patents+on+Cardiovascular+Drug+Discovery.+ 2012g7(3):2162220." 45." Eriksson"O,"Ramstrom,"M.,"Hornaeus,"K.,"Bergquist,"J.,"Mokhtari,"D.,"Siegbahn,"A."The" Eph"tyrosine"kinase"receptors"EphB2"and"EphA2"are"novel"proteolytic"substrates"of" tissue"factor/coagulation"factor"VIIa."Journal+of+Biological+Chemistry.+ 2014g289(47):32379232391." 46." Erlandsson"M,"Nielsen,"CH.,"Jeppesen,"TE.,"Kristensen,"JB.,"Petersen,"LC.,"Madsen,"J.," Kjaer,"A."Synthesis"and"characterization"of"(18)F2labeled"active"site"inhibited"factor"VII" (ASIS)."Journal+of+Labelled+Compounds+&+Radiopharmaceuticals.+2015g58(5):1962201." 47." Escobar"M,"Maahs,"J.,"Hellman,"E.,"Donkin,"J.,"Forsyth,"A.,"Hroma,"N.,"Young,"G.," Valentino,"LA.,"Tachdjian,"R.,"Cooper,"DL.,"Shapiro,"AD."Multidisciplinary"management" of"patients"with"haemophilia"with"inhibitors"undergoing"surgery"in"the"United"States:" perspectives"and"best"practices"derived"from"experienced"treatment"centres."
C23" Haemophilia.+2012g18(6):9712981." 48." Escolar"G,"Fernandez2Gallego,"V.,"Arellano2Rodrigo,"E.,"Roquer,"J.,"Reverter,"JC.," Sanz,"VV.,"Molina,"P.,"Lopez2Vilchez,"I.,"Diaz2Ricart,"M.,"Galan,"AM."Reversal"of" apixaban"induced"alterations"in"hemostasis"by"different"coagulation"factor"concentrates:" significance"of"studies"in"vitro"with"circulating"human"blood."PLoS+ONE+[Electronic+ Resource].+2013g8(11):e78696." 49." Escolar"G,"Arellano2Rodrigo,"E.,"Lopez2Vilchez,"I.,"Molina,"P.,"Sanchis,"J.,"Reverter,"JC.," Carne,"X.,"Cid,"J.,"Villalta,"J.,"Tassies,"D.,"Galan,"AM.,"Diaz2Ricart,"M."Reversal"of" rivaroxaban2induced"alterations"on"hemostasis"by"different"coagulation"factor" concentrates"2"in"vitro"studies"with"steady"and"circulating"human"blood."Circulation+ Journal.+2015g79(2):3312338." 50." Esper"R,"Estrada,"IE.,"de"la"Torre"Leon,"T.,"Gutierrez,"AO.,"Lopez,"JA."Treatment"of" diffuse"alveolar"hemorrhage"secondary"to"lupus"erythematosus"with"recombinant" activated"factor"VII"administered"with"a"jet"nebulizer."Journal+of+intensive+care.+ 2014g2(1):47." 51." Fang"R,"Markandaya,"M.,"DuBose,"JJ.,"Cancio,"LC.,"Shackelford,"S.,"Blackbourne,"LH." Early"in2theater"management"of"combat2related"traumatic"brain"injury:"A"prospective," observational"study"to"identify"opportunities"for"performance"improvement."The+Journal+ of+Trauma+and+Acute+Care+Surgery.+2015g79(4"Suppl"2):S1812187." 52." Faydhi"A,"Kassem,"YA.,"Al2Shabassy,"AM.,"Ahmed,"S.,"Al2Shareef,"A."Recombinant" activated"factor"VII"as"treatment"for"intractable"haemorrhage."Eastern+Mediterranean+ Health+Journal.+2014g19(Suppl"3):S1842189." 53." Gajsiewicz"J,"Nuzzio,"KM.,"Rienstra,"CM.,"Morrissey,"JH."Tissue"Factor"Residues"That" Modulate"Magnesium2Dependent"Rate"Enhancements"of"the"Tissue"Factor/Factor"VIIa" Complex."Biochemistry.+2015g54(30):466624671." 54." Ghai"R,"Mizuno,"CM.,"Picazo,"A.,"Camacho,"A.,"Rodriguez2Valera,"F."Key"roles"for" freshwater"Actinobacteria"revealed"by"deep"metagenomic"sequencing."Molecular+ Ecology.+2014g23(24):607326090." 55." Giordano"P,"Lassandro,"G.,"Tesse,"R.,"Longo,"S.,"Valente,"F.,"Cappiello,"AR.,"Coppola," A."Innovative"use"of"recombinant"activated"factor"VII"during"physical"rehabilitation"in"an" Italian"child"with"Glanzmann's"thromboasthenia."Blood+Transfusion.+2013g11(1):1432147." 56." Girard"T,"Tuley"E,"Broze"Jr"G."TFPIbeta"is"the"GPI2anchored"TFPI"isoform"on"human" endothelial"cells"and"placental"microsomes."Blood.+2012g119(5):125621262." 57." Godier"A,"Samama,"CM.,"Susen,"S."Management"of"massive"bleeding"in"2013:"seven" questions"and"answers."Transfusion+Clinique+et+Biologique.+2013g20(2):55258." 58." Gomez2Outes"A,"Suarez2Gea,"ML.,"Lecumberri,"R.,"Terleira2Fernandez,"AI.,"Vargas2 Castrillon,"E."Specific"antidotes"in"development"for"reversal"of"novel"anticoagulants:"a" review."Recent+Patents+on+Cardiovascular+Drug+Discovery.+2014g9(1):2210." 59." Gruber"S,"Volles,"DF."Usefulness"of"laboratory"values"in"predicting"effectiveness"of" recombinant"factor"VIIa"in"surgical"patients"with"bleeding."American+Journal+of+Health2 System+Pharmacy.+2013g70(17):152821532." 60." Guzzetta"N,"Russell,"IA.,"Williams,"GD."Review"of"the"off2label"use"of"recombinant" activated"factor"VII"in"pediatric"cardiac"surgery"patients."Anesthesia+&+Analgesia.+ 2012g115(2):3642378." 61." Hahn"N,"Heiden,"M.,"Seitz,"R.,"Salge2Bartels,"U."Inducible"expression"of"tissue"factor"in" small2cell"lung"cancer:"impact"on"morphology"and"matrix"metalloproteinase"secretion." Journal+of+Cancer+Research+&+Clinical+Oncology.+2012g138(4):6952706." 62." Han"M,"Park,"YS."Sequential"therapy"with"activated"prothrombin"complex"concentrates" and"recombinant"activated"factor"VII"to"treat"unresponsive"bleeding"in"patients"with" hemophilia"and"inhibitors:"a"single"center"experience."Blood+Research.+2013g48(4):2822 286."
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C212" tissue"factor"activity"by"thiol"redox2dependent"mechanism."Journal+of+Biological+ Chemistry.+2013g288(5):334623358." 188." Wartenberg"K,"Mayer,"SA."Ultra2Early"Hemostatic"Therapy"for"Intracerebral" Hemorrhage:"Future"Directions."Frontiers+of+Neurology+&+Neuroscience.+2015g37:1072 129." 189." Woo"C,"Patel,"N.,"Conell,"C.,"Rao,"VA.,"Faigeles,"BS.,"Patel,"MC.,"Pombra,"J.,"Akins," PT.,"Axelrod,"YK.,"Ge,"IY.,"Sheridan,"WF.,"Flint,"AC."Rapid"Warfarin"reversal"in"the" setting"of"intracranial"hemorrhage:"a"comparison"of"plasma,"recombinant"activated"factor" VII,"and"prothrombin"complex"concentrate."World+Neurosurgery.+2014g81(1):1102115." 190." Wu"B,"Zhou,"H.,"Hu,"L.,"Mu,"Y.,"Wu,"Y."Involvement"of"PKCalpha"activation"in" TF/VIIa/PAR22induced"proliferation,"migration,"and"survival"of"colon"cancer"cell"SW620." Tumour+Biology.+2013g34(2):8372846." 191." Wu"Y,"Wang,"J.,"Zhou,"H.,"Yu,"X.,"Hu,"L.,"Meng,"F.,"Jiang,"S."Effects"of"calcium"signaling" on"coagulation"factor"VIIa2induced"proliferation"and"migration"of"the"SW620"colon" cancer"cell"line."Molecular+Medicine+Reports.+2014g10(6):302123026." 192." Young"G,"Shapiro,"AD.,"Walsh,"CE.,"Gruppo,"RA.,"Gut,"RZ.,"Cooper,"DL." Patient/caregiver2reported"recombinant"factor"VIIa"(rFVIIa)"dosing:"home"treatment"of" acute"bleeds"in"the"Dosing"Observational"Study"in"Hemophilia"(DOSE)."Haemophilia.+ 2012g18(3):3922399." 193." Young"G,"Cooper,"DL.,"Gut,"RZ.,"HTRS"Investigators."Dosing"and"effectiveness"of" recombinant"activated"factor"VII"(rFVIIA)"in"congenital"haemophilia"with"inhibitors"by" bleed"type"and"location:"the"experience"of"the"Haemophilia"and"Thrombosis"Research" Society"(HTRS)"Registry"(200422008)."Haemophilia.+2012g18(6):9902996." 194." Young"G,"Teitel,"J.,"'Oiron,"R.,"eissinger,"C.,"erntorp,"E."Evaluation"of"algorithms"for"the" treatment"of"problem"bleeding"episodes"in"patients"with"hemophilia"having"inhibitors." Clinical+&+Applied+Thrombosis/Hemostasis.+2015g21(1):10218." 195." Yuan"J,"Wu,"X.,"Du,"ZY.,"Sun,"YR.,"Yu,"J.,"Li,"ZQ.,"Wu,"XH.,"Mao,"Y.,"Zhou,"LF.,"Hu,"J." Low2dose"recombinant"factor"VIIa"for"reversing"coagulopathy"in"patients"with"isolated" traumatic"brain"injury."Journal+of+Critical+Care.+2015g30(1):1162120." 196." Zatta"A,"Mcquilten,"Z.,"Kandane2Rathnayake,"R.,"Isbister,"J.,"Dunkley,"S.,"Mcneil,"J.," Cameron,"P.,"Phillips,"L."The"Australian"and"New"Zealand"Haemostasis"Registry:"ten" years"of"data"on"off2licence"use"of"recombinant"activated"factor"VII."Blood+Transfusion.+ 2015g13(1):86299." 197." Zentai"C,"Grottke,"O.,"Spahn,"DR.,"Rossaint,"R."Nonsurgical"techniques"to"control" massive"bleeding."Anesthesiology+Clinics.+2013g31(1):41253." 198." Zhang"X,"Zhu,"XL.,"Niu,"T.,"Sun,"J.,"Liu,"H.,"Feng,"R.,"Yang,"LH.,"Wei,"Q.,"Ma,"QH.," Wang,"QM.,"Feng,"FE.,"Fu,"HX.,"Mo,"XD.,"Lv,"M.,"Huang,"XJ."Combination"of"FVIII"and" low2dose"rFVIIa"improves"haemostasis"in"acquired"haemophilia"A"patients:"a" collaborative"controlled"study."Thrombosis+Research.+2015g135(5):8352840." 199." Zhu"S,"Kisiel,"W.,"Lu,"YJ.,"Petersen,"LC.,"Ndungu,"JM.,"Moore,"TW.,"Parker,"ET.,"Sun," A.,"Liotta,"DC.,"El2Rayes,"BF.,"Brat,"DJ.,"Snyder,"JP.,"Shoji,"M."Tumor"angiogenesis" therapy"using"targeted"delivery"of"Paclitaxel"to"the"vasculature"of"breast"cancer" metastases."Journal+of+Drug+Delivery.+2014g2014:865732." 200." Zhu"S,"Kisiel,"W.,"Lu,"YJ.,"Petersen,"LC.,"Ndungu,"JM.,"Moore,"TW.,"Parker,"ET.,"Sun," A.,"Sarkaria,"JN.,"Snyder,"JP.,"Liotta,"DC.,"Brat,"DJ.,"El2Rayes,"BF.,"Shoji,"M."Visualizing" cancer"and"response"to"therapy"in"vivo"using"Cy5.52labeled"factor"VIIa"and"anti2tissue" factor"antibody."Journal+of+Drug+Targeting.+2015g23(3):2572268." $
C213" Appendix$D.$Questionnaire$Sent$to$Expert$Reviewers$$ $ AHRQ%Systematic%Review%% Surveillance%Program"
$ Reviewer$Form$ $ Title$of$Original$Systematic$Review:"Comparative"Effectiveness"of"In2Hospital"Use"of" Recombinant"Factor"VIIa"for"Off2Label"Indications"vs."Usual"Care" Link"to"Report"" % Most$Recent$Surveillance$Published:"February"2012" Link"to"Surveillance"Report" + Name$of$Reviewer:"______" " Instructions:$ " The"Agency"for"Healthcare"and"Research"Quality"(AHRQ)"Scientific"Resource"Center"(SRC)" periodically"conducts"surveillance"of"published"AHRQ"systematic"reviews"to"assess"the" currency"of"review"conclusions."The"goal"of"this"process"is"to"identify"signals"that"a"report"may" be"out"of"date."One"part"of"this"process"includes"soliciting"expert"review"of"our"synthesis"of" recently"published"literature"and"previous"surveillance"assessments."" " The"original"systematic"review"was"published"in"May"2010."The"original"systematic"review" search"dates"went"through"August"2009."Previous"surveillance"was"conducted"on"February" 2012,"with"the"most"recent"search"extending"through"January"2012."We"conducted"a"bridged" literature"search"of"select"high"impact"journals"from"January"2012"to"December"2015"and" identified"evidence"potentially"related"to"the"key"questions"of"the"original"systematic"review."" " The"table"below"highlights"the"conclusions"from"the"original"systematic"review,"the"findings"and" assessment"of"the"most"recent"surveillance"assessment,+and"a"summary"of"the"relevant" recently"published"literature."Abstracts"from"relevant"literature"are"included"at"the"end"of"the" document."If"you"would"like"a"list"of"our"full"search"results,"please"let"us"know."" " Please"review"the"table"and"provide"responses"to"the"questions"for"each"key"question"below." The"primary"goal"of"this"review"is"to"identify"any"important"new"studies,"drugs,"interventions,"or" devices"you"know"of"that"we"may"have"missed"in"our"literature"search"and"to"understand"if"any" new"evidence"exists"which"may"alter"the"conclusions"of"the"original"systematic"review." " Note:"When"examining"the"studies"identified"in"the"2012"surveillance"assessment,"we"found"that" a"meta2analysis"of"35"randomized"controlled"trials"(RCTs)3"and"a"meta2analysis"of"four"RCTs11" should"not"have"been"included,"as"all"relevant"studies"were"included"in"the"original"systematic" review."The"summaries"of"key"questions"below"describe"the"impact"of"removing"these"studies"
D21" on"our"assessment"of"currency."In"addition,"descriptions"of"the"meta2analyses"are"retained"in" the"attached"table"(in"italics),"as"a"historical"record."" " Key$Question$1:" Indications,"Populations,"and"Characteristics"of"Comparative"Studies"of"Off2Label"rFVIIa"Use?"" $ Prior$Surveillance$Assessment$(2/2012)$and$Current$Literature$Analysis:$$ •" Indications"for"off2label"recombinant"Factor"VIIa"(rFVIIa)"use"were"consistent"in"the"2012" surveillance"report"as"in"the"original"systematic"review."Studies"examined"rFVIIa"use"for" intracranial"hemorrhage"(three"studies3,4,19),"body"trauma"(eight"studies3,6210,18,19),"traumatic" brain"injury"(one"study3),"and"those"undergoing"cardiac"surgery"(two"studies3,12,20)"and"liver" transplantation.11"" o" Note:"One"of"the"meta2analyses"we"excluded"upon"review11"examined"rFVIIa"for"liver" transplantation."This"was"the"only"study"examining"rFVIIa"for"liver"transplantationg" thus,"no"new"evidence"was"identified."The"second"excluded"meta2analysis,3"included" studies"examining"rFVIIa"for"intracranial"hemorrhage,"traumatic"brain"injury"(TBI)," body"trauma,"and"adult"cardiac"surgery."" •" Consistent"with"the"original"systematic"review,"the"2012"literature"search"identified"both" RCTs,4,8,9,18,21"and"observational"studies.6,7,10,12,19,20,22"One"systematic"review23"and"two+meta2 analyses3,11"were"also"identified,"although"the"meta2analyses"were"later"removed"because" all"relevant"studies"were"included"in"the"original"systematic"review.+" •" Consistent"with"the"original"systematic"review,"a"wide"range"of"ages"(24276"years"old)"and" dosages"of"rFVIIa"(52360"µg/kg"of"patient"weight)"were"represented."The"sample"size"of" included"studies"ranged"from"16918"to"1,3973"among"RCTs"and"2412"to"2,0506"in" observational"studies,"which"is"consistent"with"the"range"found"in"the"original"review.""" o" Note:"One"of"the"removed"meta2analysis3"included"a"study"of"n=1,397,"which"was" the"highest"reported"sample"size"identified"in"the"prior"surveillance"assessment." Exclusion"of"the"meta2analysis"lowers"the"upper"range"of"the"sample"size"of" identified"studies"to"n=841."No"other"changes"to"the"study"population"or" characteristics"reported"in"the"prior"assessment"resulted"from"the"removal"these" meta2analyses.3,11""""+ •" Consistent"with"the"original"systematic"review,"most"studies"reported"direct"outcomes,"such" as"thromboembolic"events3,4,6,8,10,11,19,20,23"and"mortality.628,10,11,18,21,23" $ Current$Literature$Analysis:$ •" In"general,"we"identified"indications"for"off2label"rFVIIa"use"that"were"consistent"with"the" original"systematic"review:"intracranial"hemorrhage"(one"study5),"body"trauma"(one" study13),"traumatic"brain"injury"(two"studies15,17),"liver"transplantation"(one"study16),"and" pediatric"cardiac"surgery"(one"study14)."" •" Most"of"studies"included"in"this"surveillance"report"were"observationalg"only"one"RCT5" was"identified."Sample"sizes"ranged"from"a"minimum"of"n="215"to"n=18316"individuals," which"is"lower"than"the"sample"size"found"in"the"original"review."" •" Consistent"with"the"original"review,"studies"varied"in"the"dosage"of"rFVIIa"administered," and"one"identified"study"compared"high"and"low"doses.13"" •" Consistent"with"the"original"review,"most"studies"reported"direct"outcomes,"such"as" mortality14217,24"and"thromboembolic"events"(TEs).5,13,14,24"" $ Reviewer$Questions:" 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text."
D22" " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." "" Key$Question$2:" Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing"Intracranial"Hemorrhage?" $ Prior$Surveillance$Assessment$(02/2012):$ •" Conclusions"related"to"arterial"thromboembolic"events"(TEs)"are"likely"out"of"date"due"to" “lack"of"evidence”"in"the"original"review."The"prior"surveillance"report"identified"a"meta2 analysis3"and"a"RCT4"which+found+that+that+rFVIIa+was+associated+with+higher+rates+of+ arterial+TEs+compared+to+usual+care,3"and"that"high"doses"of"rFVIIa"were"associated"with" higher"rates"of"TEs"compared"to"low"doses"and"usual"care.4"" o" It"is"our"assessment"that"the"assessment"should+have+been"that"the"original" conclusion"is"likely"current."The"original"review"included"a"meta2analysis"of"four" studies"(rated"as"moderate"strength"of"evidence)"that"found"significantly"higher" rates"of"TEs"among"high"and"medium"doses"of"rFVIIa"compared"to"usual"care" but"no"difference"among"low"doses"of"rFVIIa"compared"to"usual"care"(p."54)."" !" The"RCT4"identified"in"the"prior"assessment"is"consistent"with"the" conclusion"in"the"original"review."" !" The"identified"meta2analysis3"was"one"of"the"meta2analyses"we"excluded" due"to"all"studies"being"included"in"the"original"review."Results"of"the" meta2analysis"were"consistent"with"the"conclusions"of"the"original"reviewg" therefore,"our"exclusion"has"no"impact"on"the"assessment"of"currency." •" All"other"conclusions"are"likely"current."" $ Current$Literature$Analysis:$ •" We"identified"a"RCT5"that"found"similar"frequencies"of"deep"venous"thrombosis"when" comparing"rFVIIa"to"placebo,"and"decreased"intracerebral"hemorrhage"volumes" associated"with"rFVIIa"use"following"hematoma"evacuation."+ $ Reviewer$Questions:+ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." "" Key$Question$3a:$ Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing"Massive"Bleeding"from" Trauma?" " Prior$Surveillance$Assessment$(02/2012):" •" Conclusions"related"to"mortality"are"possibly"out"of"date."The"prior"surveillance"report" identified"four"studies629"examining"mortality."Two"studies"were"congruent"with"the" original"systematic"review’s"conclusion"of"no"difference"between"rFVIIa"and"no2rFVIIa" groups,8,9"one"RCT6"found"a"higher"mortality"rate"in"the"rFVIIa"group,"and"one"study7" found"that"among"individuals"who"received"≥"30"units"of"packed"red"blood"cells"("RBCs),"
D23" 242hour"mortality"was"lower"among"those"who"received"rFVIIa"compared"to"those"who" didn’t."" •" All"other"conclusions"are"likely"current."Findings"were"congruent"with"the"original" systematic"review’s"conclusions"related"to"TEs3,8"and"RBC"requirements.6,7,9" o" The"identified"meta2analysis3"was"one"of"the"meta2analyses"we"excluded"due"to" all"studies"being"included"in"the"original"review."Results"of"the"meta2analysis" were"consistent"with"the"conclusions"of"the"original"reviewg"therefore,"our" exclusion"has"no"impact"on"the"assessment"of"currency." " Current$Literature$Analysis:$ •" We"identified"one"study13"that"found"similar"rates"of"TEs"among"individuals"receiving" high"or"low"doses"of"rfVIIa."$ $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." $ Key$Question$3b:$"" Use"of"rFVIIa"for"Selected"Indications"in"Individuals"with/Undergoing"Massive"Bleeding"from" Trauma"(Brain"Trauma,"i.e.,"Traumatic"Brain"Injury"[TBI])?" $ Prior$Surveillance$Assessment$(02/2012):$ •" Conclusions"related"to"RBC"transfusion"are"possibly"out"of"date."No"studies"examining" the"effect"of"rFVIIa"on"RBC"transfusion"in"individuals"undergoing"massive"bleeding"from" brain"trauma"were"identified"in"the"original"systematic"review."One"identified"study10"" examining"mortality,"TEs,"and"RBC"transfusion"requirements"found"a"significant" reduction"in"RBC"use"in"the"rFVIIa"group,"and"congruent"with"the"original"systematic" review,"found"no"difference"between"groups"in"TEs"or"mortality."An+additional+meta2 analysis3+also+found+no+difference+between+groups+on+arterial+TEs.+All"other"conclusions" are"likely"current."" o" The"identified"meta2analysis3"was"one"of"the"meta2analyses"we"excluded"due"to" all"studies"being"included"in"the"original"review."Results"of"the"meta2analysis" were"consistent"with"the"conclusions"of"the"original"reviewg"therefore,"our" exclusion"has"no"impact"on"the"assessment"of"currency." $ Current$Literature$Analysis:$ •" We"identified"two"studies"examining"mortality"comparing"rFVIIa"to"no2rFVIIa"that"found" no"difference"between"groups.15,17"+ •" One"study15"also"found"no"occurrence"of"TEs"in"either"group"and"no"difference"between" groups"on"length"of"intensive"care"unit"(ICU)"stay."+ $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?"" Click"here"to"enter"text." "
D24" 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." " Key$Question$4a:$" Use"of"rFVIIa"for"Selected"Indications"in"Individuals"With/Undergoing"Liver"Transplantation?"" $ Prior$Surveillance$Assessment$(02/2012):$ •" The"original"review’s"conclusion"of"a"trend"towards"reduced"RBC"transfusion" requirements"with"rFVIIa"compared"to"usual"care"is"possibly"out"of"date."One+meta2 analysis11+was+identified,+which+examined+the+effect+of+rFVIIa+for+RBC+transfusions+and+ mortality+and+found+that+found+no+significant+difference+between+groups.+" o" The"identified"meta2analysis11"was"one"of"the"meta2analyses"we"excluded"due"to" all"studies"being"included"in"the"original"review."Of"note,"two"of"the"studies"from" the"meta2analysis"were"included"in"the"original"review"for"liver"transplantation," and"two"were"included"for"other"surgery."No"other"studies"examining"rFVIIa"use" on"RBC"transfusions"were"identifiedg"therefore,"it"is"our"assessment"that"the"prior" surveillance"should"have"determined"that"the"conclusions"were"likely"current." Conclusions"related"to"mortality"are"likely"current." •" All"other"conclusions"are"likely"current."" $ Current$Literature$Analysis:$ •" We"identified"one"study16"that"found"that"individuals"receiving"rFVIIa"before"surgery"had" longer"ICU"stays"compared"to"usual"care."In"addition,"those"who"received"rFVIIa" intraoperatively"required"more"blood"products"and"had"higher"mortality"(30"days"and"one" year)"compared"to"individuals"receiving"rFVIIa"preemptively"and"those"receiving"usual" care.$ $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." " Key$Question$4b.i:$$$ Use"of"rFVIIa"for"Selected"Indications"in"Individuals"with/Undergoing"Cardiac"Surgery"(Adult" Cardiac"Surgery)?" $ Prior$Surveillance$Assessment$(02/2012):$ •" Conclusions"are"likely"current."The"previous"surveillance"report"identified"a+meta2 analysis+examining+TEs.3"Findings"were"consistent"with"the"original"review"and"found"no" difference"between"groups."In"addition,"also"consistent"with"the"original"review,"one" identified"study"reported"no"data"on"operating"room"time.12"" o" The"identified"meta2analysis3"was"one"of"the"meta2analyses"we"excluded"due"to" all"studies"being"included"in"the"original"review."Results"of"the"meta2analysis" were"consistent"with"the"conclusions"of"the"original"reviewg"therefore,"our" exclusion"has"no"impact"on"the"assessment"of"currency." $
D25" Current$Literature$Analysis:$ •" No"new"studies"were"identified.$ $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." $ Key$Question$4b.ii:$$$ Use"of"rFVIIa"for"Selected"Indications"in"Individuals"with/Undergoing"Cardiac"Surgery"(Pediatric" Cardiac"Surgery)?" $ Prior$Surveillance$Assessment$(02/2012):$ •" Conclusions"are"likely"current."One"study,20"congruent"with"the"original"systematic" review’s"conclusions,"found"no"difference"between"groups"in"mortality,"TEs,"and"RBCs" transfusion"requirements.""" $ Current$Literature$Analysis:" •" We"identified"one"study14"that"found"no"significant"difference"between"individuals" administered"rFVIIa"before"or"after"surgery"compared"to"a"matched"no2rFVIIa"group"on" mortality"or"rate"of"thrombosis."" $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text." $ Key$Question$4c:$$$$ Use"of"rFVIIa"for"Selected"Indications"in"Individuals"with/Undergoing"Prostatectomy?" $ Prior$Surveillance$Assessment$(02/2012):$ •" Conclusions"are"likely"current."No"new"studies"were"identified."" $ Current$Literature$Analysis:" •" No"new"studies"were"identified."$ $ Reviewer$Questions:$ 1." Are"the"original"report"conclusions"still"supported"by"the"current"evidence?" Click"here"to"enter"text." " 2." Are"there"any"published"or"unpublished"studies"that"you"know"of"that"we"may"have" overlooked?"" Click"here"to"enter"text."
D26" Original(Systematic(Review(Conclusions(and(Literature(Analysis( ( Title(of(Original(Systematic(Review:(Comparative$Effectiveness$of$In"Hospital$Use$of$Recombinant$Factor$VIIa$for$Off"Label$ Indications$vs.$Usual$Care( ( Original(Systematic(Review(Published:(May$2010( Original(Systematic(Review(Search(Dates:(Key$Question$1:$2008"2008$in$Premier$databaseK$Key$Questions$2"4:$Database$ inception"August$2009( ! Most(Recent(Surveillance(Report(Published:(February$2012( Most(Recent(Surveillance(Report(Search(Dates:(January$2008"January$2012( ! Current(Literature(Search(Dates:(January$2012"December$2015( $ The$conclusions$from$the$original$systematic$review,$the$findings$and$assessment$of$the$most$recent$surveillance$assessment$and$a$ summary$of$the$relevant$recently$published$literature.$Abstracts$are$provided$at$the$end$of$the$document.$ $ Table$1.$Key$Question$1:$Indications,$Populations,$and$Characteristics$of$Comparative$Studies$of$Off"Label$rFVIIa$Use?$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Indications(and(populations(of(comparative( Indications(and(populations(of(comparative( Indications(and(populations(of(comparative( studies:( studies:( studies:( Off"label$rFVIIa$use$was$examined$in$24$RCTs$ Indications$for$off"label$rFVIIa$use$were$ In$general,$we$identified$indications$for$off"label$ and$31$comparative$observational$studies$ consistent$in$the$2012$surveillance$report$as$in$ rFVIIa$use$that$were$consistent$with$the$ across$a$variety$of$clinical$indications,$ the$original$systematic$review.$Studies$ original$systematic$review:$intracranial$ including$cardiac$surgery$(12$studies),$trauma$ examined$rFVIIa$use$for$intracranial$ hemorrhage$(one$study5),$body$trauma$(one$ (nine$studies),$intracranial$hemorrhage$(ICH)$ hemorrhage$(three$studies3,4,19),$body$trauma$ study13),$traumatic$brain$injury$(two$ (eight$studies),$liver$transplantation$(eight$ (eight$studies3,6<10,18,19),$traumatic$brain$injury$ studies15,17),$liver$transplantation$(one$study16),$ studies),$and$prostatectomy$(one).$These$ (one$study3)$and$those$undergoing$cardiac$ and$pediatric$cardiac$surgery$(one$study14).$$ studies$accounted$for$69%$of$the$included$off" surgery$(two$studies3,12,20)$and$liver$ $ label$rFVIIa$studies.$There$were$prominent$ transplantation11.$$ Characteristics(of(comparative(studies:( community$uses$that$lacked$studies,$such$as$ $ Most$of$studies$included$in$this$surveillance$ primary$clotting$disorders$other$than$ Characteristics(of(comparative(studies:$ report$were$observationalK$only$one$RCT5$was$ hemophilia,$secondary$clotting$disorders,$and$ Consistent$with$the$original$systematic$review,$ identified.$Sample$sizes$ranged$from$a$ gastrointestinal$bleeding$not$related$to$liver$ the$2012$literature$search$identified$both$ minimum$of$n=$215$to$n=18316$individuals,$ disease.$Other$indications$with$no$studies$ RCTs4,8,9,18,21,$and$observational$ which$is$lower$than$the$sample$size$found$in$
D"7$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! included$aortic$aneurysm,$other$vascular$ studies6,7,10,12,19,20,22.$One$systematic$review23$ the$original$review.$Consistent$with$the$original$ procedures,$and$neonatal$use$(beyond$cardiac$ and$two$meta D"8$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcome:(Mortality((90(day)( Assessment:(Current( No$studies$were$identified.$$ SOE:(Moderate( An$expert$reviewer$suggested$an$article25$on$ Four(RCTs,(one(comparative(observational( using$rFVIIa$to$treat$cerebral$hemorrhage$in$ study( acute$promyelocytic$leukemia$individuals,$but$it$ Meta"analysis$found$no$effect$of$rFVIIa$on$ did$not$meet$inclusion$criteria$(was$not$a$ mortality$(risk$difference:$low"dose$group:$ randomized$or$observational$study).$ 0.031$[95%$CI$"0.086$to$0.024],$medium"dose$ group:$0.020$[95%$CI$"0.076$to$0.036],$high" dose$group:$0.027$[95%$CI$"0.121$to$0.068]).$ No$difference$in$mortality$was$found$in$the$ observational$study.$ Outcome:(Arterial(Thromboembolic(Events( Assessment:(Current*( No$studies$were$identified.$ (Arterial(TEs)( Two$studies$examined$the$association$ SOE:(Moderate( between$rFVIIa$use$and$risk$of$arterial$ Four(RCTs,(one(comparative(observational( thromboembolic$events$(arterial$TEs).$$ study( •$ One$RCT4$(n=841)$demonstrated$an$ Meta"analysis$found$significantly$higher$rates$ association$between$higher$doses$of$rFVIIa$ of$arterial$thromboembolic$events$with$medium$ and$arterial$TEs$as$compared$to$no"rFVIIa$ and$high$doses$of$rFVIIa$compared$to$usual$ group$(odds$ratio=2.14K$p=0.031).$$ care,$and$a$similar,$but$non"significant,$finding$ •$ A$meta D"9$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! 4(RCTs( Meta"analysis$found$no$effect$of$rFVIIa$on$ modified$Rankin$Scale$(mRS)$(risk$difference:$ low$dose$"0.024$[95%$CI$"0.093$to$0.045],$ medium$dose$"0.029$[95%$CI$"0.099$to$0.041],$ high$dose$"0.040$[95%$CI$"0.154$to$0.075]).$ Outcome:(Change(in(Hematoma(volume( Assessment:(Current( A$RCT5$(n=21)$among$individuals$receiving$ SOE:(Moderate( No$studies$were$identified.$ surgery$for$spontaneous$supratentorial$ Four(RCTs( intracerebral$hemorrhage$compared$the$use$of$ Meta"analysis$found$significant$reductions$in$ rFVIIa$(100$mcg/KG$b.w.)$to$placebo$and$ relative$hematoma$expansion$in$the$rfVIIa$ found$similar$reductions$in$intracerebral$ group$compared$to$usual$care$at$all$dosing$ hemorrhage$volumes$following$hematoma$ levels$(standardized$mean$difference:$low$dose$ evacuation$at$18"30$hours$(mean$difference$ "0.146$[95%$CI$"0.291$to$"0.001],$medium$dose$ 2.1$mL,$95%$confidence$interval$"12.1$to$16.2,$ "0.240$[95%$CI$"0.385$to$"0.095],$high$dose$" P=0.76$[0.03$mL$after$adjustment$for$baseline$ 0.334$[95%$CI$"0.579$to$"0.090]).$$ value]).$$ Abbreviations:$BW=By$WeightK$CI=Confidence$IntervalK$mRS=Modified$Rankin$ScaleK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$ Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ *$Indicates$the$assessment$of$currency$was$changed$from$“possibly$out$of$date”$to$“current”$in$the$current$review$due$to$the$removal$of$the$two$ meta"analyses3,11$whose$results$were$previously$included$in$the$original$systematic$review.$$ $ Table$3.$Key$Question$3a:$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Massive$Bleeding$from$Trauma$(Body$Trauma)$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcome:(Mortality((30(days)( Assessment:(Possibly(out(of(date! No$studies$were$identified.$ SOE:(Low( Three$RCTs$and$one$observational$study$ Two(RCTs,(three(comparative(observational( examined$mortality$rates$associated$with$ studies( rFVIIa$versus$no"rFVIIa$groups.$$ •$ Among$individuals$who$survived$at$least$48$ •$ One$RCT$recommend$by$an$expert$ hours,$RCTs$note$no$difference$between$ reviewer8$(n=560)$compared$rFVIIa$use$to$ rfVIIa$and$usual$care$in$30"day$mortality.$ placebo$and$found$no$significant$difference$ Evidence$from$observational$studies$ in$30"day$mortality$between$groups$(12.2%$ weakly$favored$rFVIIa.$( vs$11.1%K$p=$0.61).$ D"10$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Of$note,$studies$had$differing$exclusion$criteria$ •$ A$second$RCT6$(n=2,050)$found$similar$ for$48"hour$mortality,$and$none$of$them$were$ mortality$rates$among$rFVIIa$and$no"rFVIIa$ sufficiently$powered$to$detect$differences$in$30" groups$(20.0%$vs$14.3%K$p>0.05).$ day$mortality.$ However,$this$study$also$demonstrated$ significantly$increased$mortality$rate$with$ the$use$of$rFVIIa$in$regression$analysis$ (OR:$1.67,$95%$CI:$1.08$to$2.60K$p=0.02).$$ •$ A$third$RCT9$(n=573)$found$no$difference$ in$30"day$mortality$between$rFVIIa$and$no" rFVIIa$groups$for$individuals$with$blunt$ trauma$(11.0%$vs10.7%,$p=$0.93)$or$for$ individuals$with$penetrating$trauma$(18.2%$ vs13.2%K$p=$0.40).$$ A$retrospective$cohort$study$recommended$by$ an$expert$reviewer7$found$no$difference$in$ mortality$for$rFVIIa$compared$to$no"rFVIIa$in$ terms$of$transfusions$less$than/equal$to$20$ units$(24"hour:$25%$vs$24%K$30"day:$25%$vs$ 42%)$or$21$to$30$units$(24"hour:$33%$vs$47%,$ 30"day:$55%$vs$50%).$However,$for$initial$ requirement$of$more$than/equal$to$30$units$of$ RBCs,$24"hour$mortality$(26%$vs$64%,$P$=$ 0.02)$was$significantly$decreased$in$individuals$ that$received$rFVIIa$compared$with$those$who$ did$not.$These$mortality$differences$were$not$ maintained$at$30$days$(68%$vs$71%).$$ Outcome:(Thromboembolic(Events((TEs)( Assessment:(Current! A$retrospective$cohort$study13$(n=152)$of$ SOE:(Low( Two$studies$found$no$difference$between$ individuals$receiving$off$label$rFVIIa$in$a$large$ Two(RCTs,(three(comparative(observational( rFVIIa$and$no"rFVIIa$groups$on$risk$of$TEs.$$ academic$center$(2005"2012)$compared$rates$ studies( •$ A$meta D"11$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcome:(Units(of(RBCs(Transfused( Assessment:(Current! No$studies$were$identified.$ SOE:(Low( A$RCT$and$two$observational$studies$ Two(RCTs,(one(comparative(observational( examined$units$of$RBCs$transfused$for$rFVIIa$ studies( vs$no"rFVIIa$groups$ •$ For$blunt$trauma$individuals,$one$RCT$ •$ A$RCT9$(n=573)$found$that$blunt$trauma$ found$a$significant$reduction$in$RBC$ individuals$who$received$rFVIIa$used$ transfusions$for$rFVIIa$compared$to$no" significantly$fewer$RBC$units$over$48$hours$ rFVIIa.$Another$RCT$among$penetrating$ compared$to$no"rFVIIa$group$(\(mean±SD)$ trauma$individuals$found$similar$but$non" 7.8$±$10.6$versus$9.1±11.3K$p=$0.04).$ significant$reductions$in$RBC$transfusions.$ However,$penetrating$trauma$individuals$ The$observational$study$found$an$increase$ who$received$rFVIIa$had$non"significantly$ in$transfusion$requirements$associated$ reduced$RBC$units$over$48$hours$ with$rFVIIa$compared$to$usual$care.$$ compared$to$no"rFVIIa$(5.0±7.4$versus$6.8$ Of$note,$comparisons$across$studies$are$ ±$6.9K$p=$0.11.7)$$ difficult$due$to$differing$exclusion$criteria$for$ •$ A$retrospective$cohort$study$7$(n=228)$ early$in"hospital$mortality.$$ recommend$by$an$expert$reviewer$ examined$rFVIIa$compared$to$no"rFVIIa$ among$massively$transfused$individuals.$ The$study$found$reduced$RBC$units$in$ rFVIIa$compared$to$no"rFVIIa$over$6$hours$ (mean:$35.6±2.6$vs.$25.6±0.7K$p=0.001)$ and$24$hours$(mean:$38.6±2.9$vs.$ 28.0±1.0K$p=0.00).$$ Another$retrospective$cohort$study6$found$no$ difference$between$those$who$received$rFVIIa$ and$no"rFVIIa$in$the$number$and$range$of$RBC$ units$used$(number(range)K$rFVIIa:$10(6–16)$$ vs$no"rFVIIa$10(4–17)K$p D"12$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! and$the$observational$study$together$ suggested$a$trend$in$the$same$direction.$( Event$rates$for$ARDS$were$low,$so$the$studies$ were$likely$underpowered$to$detect$any$ difference$between$groups.$ Abbreviations:$ARDS=Acute$Respiratory$Distress$SyndromeK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa" Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ $ Table$4.$Key$Question$3b.$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Massive$Bleeding$from$Trauma$(Brain$Trauma)$ i.e.,$Traumatic$Brain$Injury$[TBI])$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcome:(Mortality((15(days)(( Assessment:(Current$ Two$studies$found$no$difference$between$ SOE:(Low( A$retrospective$cohort$study10$(n=28)$found$no$ rFVIIa$and$no"rFVIIa$groups$on$mortality.$$ One(RCT,(one(comparative(observational( significant$differences$between$rFVIIa$and$no" •$ A$retrospective$cohort$study15$(n=86)$ study( rFVIIa$on$mortality$(50%$vs$29%K$p=0.22).$$ found$no$significant$difference$between$ •$ The$RCT$found$no$difference$between$ individuals$who$received$low"dose$rFVIIa$ groups$in$mortality$at$15$days,$with$rates$of$ and$matched$no"rFVIIa$groups$on$ 11%$in$each$group.$The$observational$ mortality.$$ study$found$a$reduced$mortality$with$rFVIIa$ •$ A$prospective$cohort$study17$(n=87)$of$ compared$to$usual$care$but$this$was$a$non" individuals$with$TBI$and$coagulopathy$ significant$finding:$33.3%$vs$52.9%$in$the$ found$a$non"significant$reduction$in$ two$groups,$respectively.$$ mortality$among$those$who$received$low" •$ The$findings$in$both$studies$are$limited$by$ dose$rFVIIa$therapy$compared$to$no" low$event$rates.$$ rFVIIa.$$ Outcome:(Thromboembolic(events((TEs)( Assessment:(Current$ A$retrospective$cohort$study15$(n=86)$found$no$ (72(hours)(( Two$studies$assessed$the$association$between$ occurrence$of$thromboembolic$events$in$either$ SOE:(Low( rFVIIa$and$TEs$as$compared$to$no"rFVIIa$ rFVIIa$or$matched$no"rFVIIa$groups.$$ One(RCT,(one(comparative(observational( groups.$$ $ study( •$ A$meta D"13$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! rFVIIa$group$consisted$of$deep$vein$ •$ A$retrospective$cohort$study10$(n=28)$of$ thrombosis,$all$of$which$were$symptomatic.$ individuals$with$TBI$undergoing$emergent$ The$observational$study$found$TE$event$ craniotomy$reported$no$TE$complications$in$ rates$in$rFVIIa$vs$usual$care$were$22.2%$ either$the$rFVIIa$or$no"rFVIIa$groups.$$ and$17.6%$respectively.$One$of$these$ events$was$deep$vein$thrombosis,$which$ occurred$in$the$usual$care$group.$$ •$ The$findings$in$both$studies$are$limited$ by$low$event$rates.$ Outcome:(Hematoma(volume(change( Assessment:(Current$ No$studies$were$identified.$ SOE:(Low( No$studies$were$identified.$$ One(RCT( •$ One$RCT$found$a$non"significant$reduction$ in$hematoma$volume$change$in$the$rFVIIa$ group$compared$to$no"rFVIIa$group$(7.0$ mL$(SD$12.9)$versus$10.4$mL$(25.0),$ respectively).$ Outcome:(RBC(Transfusion(Requirement( Assessment:(Possibly(out(of(date$ No$studies$were$identified.$ No$studies$reported$on$this$outcome.$$$ An$retrospective$study10$(n=28)$among$ individuals$with$TBI$undergoing$emergent$ craniotomy$found$a$significant$reduction$of$ RBC$units$in$individuals$receiving$rFVIIa$ versus$no"rFVIIa$(median(range)$of$units:$ preoperative:$0$(0–2)$versus$4$(2–8)K$p=$0.001K$$ intraoperative:$1$(0–2)$versus$5$(2–8)$K$ p=0.002K$postoperative:$1$(0–2)$versus$3$(2–5)K$ p=$0.002K$and$total:$4$(1–5)$versus$14$(10–17)K$ p=$0.001.)$ Outcome:(ICU(length(of(stay( No$studies$were$identified.$ A$retrospective$cohort$study15$(n=86)$found$no$ No$studies$reported$on$this$outcome.$$ significant$difference$between$individuals$who$ received$low"dose$rFVIIa$and$matched$no" rFVIIa$individuals$on$length$of$ICU$stay.$ Abbreviations:$ICU=Intensive$Care$UnitK$RCB=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialsK$rFVIIa=Recombinant$Factor$Seven" AK$SD=Standard$DeviationK$SOE=Strength$of$EvidenceK$TBI=Traumatic$Brain$InjuryK$TE=Thomboembolic$EventK$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ D"14$ $ Table$5.$Key$Question$4a:$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Liver$Transplantation$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcomes:(Mortality( Assessment:(Current( An$retrospective$cohort$study16$(n=183)$ SOE:(Low( A$meta D"15$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! transplantation$taking$over$200$minutes$less$in$ the$rFVIIa$group$compared$to$placebo.$None$ of$the$other$studies$identified$a$significant$ difference$between$groups$ Outcomes:(ICU(length(of(stay( Assessment:(Current$$ An$retrospective$cohort$study16$(n=183)$ SOE:(Low( No$studies$were$identified.$ compared$the$use$of$rFVIIa$preemptively$or$ Three(RCTs( intraoperatively$to$a$matched$no"rFVIIa$group$ Three$RCTs$found$no$difference$between$ and$found$that$individuals$who$received$rFVIIa$ groups$in$ICU$length$of$stay.$$ intraoperatively$had$longer$ICU$stays$than$ $ those$receiving$rFVIIa$preemptively$or$the$no" rFVIIa$group.$ Abbreviations:$CI=Confidence$IntervalK$ICU=Intensive$Care$UnitK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$ rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ *Indicates$the$assessment$of$currency$was$changed$from$“possibly$out$of$date”$to$“current”$in$the$current$review$due$to$the$removal$of$the$two$ meta"analyses3,11$whose$results$were$previously$included$in$the$original$systematic$review.$$ $ Table$6.$Key$Question$4b.i.$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Cardiac$Surgery$(Adult$Cardiac$Surgery)$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcomes:(Mortality((inWhospital)( Assessment:(Current$$ No$studies$were$identified.$ SOE:(Low( No$studies$were$identified.$ Two(RCTs,(four(comparative(observational( studies,(four(metaWanalyses( Meta"analysis$of$good"quality$RCTs$and$ observational$studies$found$no$difference$in$ mortality$between$rFVIIa$and$usual$care$(risk$ difference$0.007K$95%$CI$"0.049$to$0.063)$ Outcomes:(Thromboembolic(events( Assessment:(Current$$ No$studies$were$identified.$ SOE:(Moderate( A$meta D"16$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! thromboembolic$events$in$the$rFVIIa$group$ compared$to$the$no"rFVIIa$group$(risk$ difference$0.053K$95%$CI$0.01$to$0.096)$ Outcomes:(Units(of(RBCs(transfused(in(24( Assessment:(Current$$ No$studies$were$identified.$ hours( No$studies$were$identified.$ SOE:(Low( One(RCT,(three(comparative(observational( studies( A$RCT$and$a$good$quality$observational$study$ found$a$non"significant$and$significant$ difference$between$groups$that$favored$rFVIIa$ use$over$no"rFVIIa$groups,$respectively$(p$ values$0.11$and$<0.001).$One$additional$ observational$study$found$no$difference$ between$groups,$and$another$found$a$ significant$effect$against$the$rFVIIa$group$(i.e.,$ increased$transfusions$with$treatment).$ Outcomes:(ICU(length(of(stay( Assessment:(Current$$ No$studies$were$identified.$ SOE:(Low( No$studies$were$identified.$$ One(RCT,(four(comparative(observational( $ studies( $ One$RCT$found$no$significant$difference$ between$groups$in$ICU$length$of$stay.$Findings$ among$observational$studies$were$ inconsistent:$one$cohort$study$found$a$ significantly$longer$ICU$length$of$stay$for$ rFVIIa$individuals$but$two$others$had$ significant$and$non"significant$findings$in$the$ opposite$direction,$respectively.$A$fourth$cohort$ study$found$no$difference$between$groups.$ Outcome:(Operating(room(time( Assessment:(Current( No$studies$were$identified.$$ No$studies$reported$on$this$outcome.$ A$retrospective$chart$review12$(n=24)$ recommended$by$an$expert$reviewer$reported$ lesser$median$operating$room$time$for$rFVIIa$ group$versus$reoperation$for$refractory$ bleeding$after$surgery$group,$however,$the$ data$were$not$reported.$ D"17$ Abbreviations:$CI=Confidence$IntervalK$ICU=Intensive$Care$UnitK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$ rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ $ Table$7.Key$Question$4b.ii.$Use$of$rFVIIa$for$Selected$Indications$in$Patient$With/Undergoing$Cardiac$Surgery$(Pediatric$Cardiac$Surgery)$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)$ Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcomes:(Mortality((inWhospital)( Assessment:(Current$ A$retrospective$matched$case"control$study$14$ SOE:(Insufficient( A$retrospective$matched$case"control$study$20$ (n=135)$of$individuals$who$received$rFVIIa$ No$studies$were$identified.$$ (n=75)$found$no$significant$difference$between$ (during$or$after$cardiac$surgery)$and$matched$ $ individuals$receiving$rFVIIa$and$a$matched$no" no"rFVIIa$group$found$no$significant$ rFVIIa$group$on$mortality.$ differences$in$mortality$rates$(16%$vs$9.5%,$ p=.208).$ Outcomes:(Thromboembolic(events( Assessment:(Current$ A$retrospective$matched$case"control$study$14$ SOE:(Insufficient( A$retrospective$matched$case"control$20$(n=75)$ (n=135)$of$individuals$who$received$rFVIIa$ One(RCT( found$no$significant$differences$between$ (during$or$after$cardiac$surgery)$and$matched$ One$RCT$identified$no$thromboembolic$events$ individuals$receiving$rFVIIa$and$a$matched$no" no"rFVIIa$group$found$no$significant$ in$either$rFVIIa$or$usual$care$groups.$$ rFVIIa$group$on$rate$of$TE$(8%$versus$4%K$ differences$in$the$rate$of$thrombosis$(20%$vs$ p=NR).$$ 28%,$p=.540).$$ Outcomes:(Units(of(Whole(BIood/RBC( Assessment:(Current$ No$studies$were$identified.$ transfusion( A$retrospective$matched$case"control$20$(n=75)$ SOE:(Insufficient( found$no$significant$differences$between$ One(RCT( individuals$receiving$rFVIIa$and$a$matched$no" One$RCT$found$a$non"significant$decrease$in$ rFVIIa$group$on$RBC$transfusion$requirements$ transfusion$requirements$for$RBCs$and/or$ (93.2$mL/kg$versus$108.3$mL/kgK$p$=$0.225).$$ whole$blood$in$the$rFVIIa$group$compared$to$ no"rFVIIa$groups.$$ Outcomes:(Time(to(chest(closure( Assessment:(Current$ No$studies$were$identified.$ SOE:(Insufficient( No$studies$were$identified.$ One(RCT( One$RCT$found$that$rFVIIa$individuals$had$a$ longer$time$to$chest$closure$than$did$no"rFVIIa$ groups$(98.8$minutes$(SE$27.3)$versus$58.3$ minutes$(SE$29.2),$p=0.026).$$ Abbreviations:$NR=Not$ReportedK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$Factor$Seven"AK$ SE=Standard$ErrorK$SOE=Strength$of$Evidence$ ( D"18$ Table$8.$Key$Question$4c.$Use$of$rFVIIa$for$Selected$Indications$in$Patient$With/Undergoing$Prostatectomy$ Conclusions(From(Original(Systematic( Findings(and(Assessment(from(Most( Literature(Analysis((December(2015)( Review((May(2010)(Link(to(report( Recent(Surveillance(Assessment((February( 2012)!Link(to(report! Outcomes:(Mortality((10(day)( Assessment:(Current$ No$studies$were$identified.$ SOE:(Insufficient( No$studies$were$identified.$ One(RCT( One$RCT$reported$no$deaths$in$either$rFVIIa$or$ no"rFVIIa$groups.$( Outcomes:(Thromboembolic(events( Assessment:(Current$ No$studies$were$identified.$ SOE:(Insufficient(( No$studies$were$identified.$ One(RCT( One$RCT$reported$a$single$TE$(myocardial$ infarction)$in$the$20$μg/kg$dose$of$rFVIIa$group.$( Outcomes:(Units(of(RBCs(transfused( Assessment:(Current$ No$studies$were$identified.$ SOE:(Insufficient( No$studies$were$identified.$ One(RCT( One$RCT$found$significantly$reduced$RBC$ transfusion$requirements$in$the$rFVIIa$group$ compared$to$usual$care.$( Outcomes:(Operative(Room(time( Assessment:(Current$ No$studies$were$identified.$ SOE:(Insufficient( No$studies$were$identified.$ One(RCT( One$RCT$found$significantly$reduced$operating$ room$time$in$the$rFVIIa$group$compared$to$ usual$care( Abbreviations:$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$ EvidenceK$TE=Thromboembolic$Event( ( Abstracts(from(Relevant(Literature/References(( $ 17.$Bucklin,$M.$H.,$et$al.$(2014).$"The$effects$of$recombinant$activated$factor$VII$dose$on$the$incidence$of$thromboembolic$events$in$ patients$with$coagulopathic$bleeding."$Thromb$Res$133(5):$768"771.$ $ INTRODUCTION:$Previous$studies$have$suggested$the$used$of$off"label$recombinant$factor$VII$(rFVIIa)$increases$the$risk$of$ thromboembolic$events,$but$the$effect$of$the$dose$of$rFVIIa$is$not$well$described$in$the$literature.$MATERIALS$AND$METHODS:$All$ adult$patients$that$received$off"label$rFVIIa$from$2005"2012$were$included$in$this$single"center,$retrospective$cohort$study.$The$ primary$endpoint$was$the$incidence$of$a$thromboembolic$event$in$the$low$dose$(<50$mcg/kg)$compared$to$the$high$dose$(>/=50$ D"19$ mcg/kg)$cohort.$Secondary$endpoints$compared$time$to$thromboembolic$event,$incidence$of$arterial$compared$to$venous$events,$and$ mortality.$RESULTS:$There$were$152$patients$that$received$rFVIIa$during$the$study$period$with$66$in$the$low$dose$cohort$and$86$in$ the$high$dose$cohort.$Mean$total$dose$of$rFVIIa$was$30.2$mcg/kg$(SD$+/"$9.5$mcg/kg)$in$the$low$dose$and$99.8$mcg/kg$(SD$+/"$64.7$ mcg/kg)$in$the$high$dose$cohort$(p=0.0001).$The$overall$incidence$of$thromboembolic$events$was$12.5%.$There$were$12$(14%)$ events$in$the$low$dose$cohort$and$seven$(10.6%)$in$the$high$dose$cohort,$RR=0.76$(95%$CI$0.31"1.82).$There$were$no$differences$in$ any$of$the$secondary$outcomes.$A$higher$incidence$of$thromboembolic$events$in$cardiothoracic$surgery$(20.8%)$and$penetrating$ trauma$patients$(21.4%)$was$seen$compared$to$the$remaining$cohort$(6.7%).$CONCLUSIONS:$No$significant$difference$in$the$ incidence$of$thromboembolic$events$was$seen$between$low$dose$versus$high$dose$rFVIIa$over$a$seven$year$period$at$our$institution.$ However,$due$to$the$relatively$low$overall$incidence$and$a$small$sample$size,$type$II$error$may$be$present.$ $ $ 16.$Imberti,$R.,$et$al.$(2012).$"Intraoperative$intravenous$administration$of$rFVIIa$and$hematoma$volume$after$early$surgery$for$ spontaneous$intracerebral$hemorrhage:$a$randomized$prospective$phase$II$study."$Minerva$Anestesiol$78(2):$168"175.$ $ BACKGROUND:$Surgery$of$spontaneous$supratentorial$intracerebral$hemorrhage$(ICH),$especially$if$performed$early,$can$be$ complicated$by$rebleeding,$a$condition$that$can$worsen$the$outcome.$We$evaluated$the$effect$of$recombinant$activated$factor$VII$ (rFVIIa)$on$postoperative$rebleeding.$METHODS:$In$this$randomized,$open"label,$single"blinded$study,$21$patients$with$spontaneous$ supratentorial$ICH$diagnosed$by$computed$tomography$(CT)$scan$were$treated$with$intravenous$rFVIIa$(100$mcg/Kg$b.w.,$N=13)$or$ placebo$(N=8).$Hematoma$volume$was$assessed$using$CT$scan$immediately,$18"30$hours,$and$5"7$days$after$hematoma$ evacuation.$The$primary$endpoint$was$a$hematoma$volume$at$18"30$hours$after$surgery.$All$CT$scans$were$evaluated$at$one$center$ by$the$same$investigator$who$was$unaware$of$the$treatment.$Hematoma$volume$was$measured$using$dedicated$software.$ RESULTS:$At$baseline,$the$hematoma$volume$was$59.2+/"27.4$and$71.5+/"32.1$mL$in$the$rFVIIa$and$placebo$group,$respectively.$ Hematoma$evacuation$resulted$in$significantly$smaller$ICH$volumes$that$were$similar$in$the$rFVIIa$and$placebo$group$at$18"30$hours$ after$surgery$(15.9+/"14.2$mL$and$18+/"15.1$mL,$respectivelyK$mean$difference$2.1$mL,$95%$confidence$interval$"12.1$to$16.2,$P=0.76$ (0.03$mL$after$adjustment$for$baseline$value)).$The$frequencies$of$deep$venous$thrombosis,$myocardial$infarction,$troponin$I$ elevation$and$cerebral$ischemia$were$similar$in$both$groups.$CONCLUSION:$In$this$pilot$study,$intraoperative,$intravenous$rFVIIa$ administration$did$not$modify$hematoma$volume$after$early$ICH$surgery.$However,$the$95%$CI$was$wide,$which$indicates$ considerable$uncertainty.$Therefore,$our$results$do$not$disprove$the$potential$benefit$of$rFVIIa$administration,$which$could$be$shown$ in$a$larger$study.$ $ $ 21.$Martinez$Lopez,$M.$C.,$et$al.$(2013).$"[Risk$assessment$of$thrombotic$events$after$the$use$of$activated$factor$VII]."$An$Pediatr$ (Barc)$79(3):$177"181.$ $ INTRODUCTION:$The$objective$of$this$study$was$to$analyze$the$incidence$of$thrombotic$complications$related$to$recombinant$human$ factor$viia$(rFVIIa)$therapy$for$severe$postoperative$bleeding$in$cardiac$surgery.$MATERIAL$AND$METHODS:$A$retrospective$ D"20$ matched$case"control$study$was$conducted$over$two$years,$including$72$children$admitted$to$intensive$care$unit$and$treated$with$ rFVIIa$because$of$a$severe$bleeding$during$or$after$cardiac$surgery.$A$control$group$of$63$patients$was$chosen,$who$were$statistically$ comparable$in$sex,$weight,$diagnosis,$surgical$risk$according$RASCH"1$score,$and$surgical$characteristics,$was$chosen.$RESULTS:$ There$were$no$significant$differences$between$cases$and$controls$either$in$the$rate$of$thrombosis$(20%$vs$28%,$P=.540),$or$in$the$ mortality$rate$(16%$vs$9.5%,$P=.208).$CONCLUSIONS:$In$our$study,$the$rFVIIa$therapy$was$shown$to$be$useful$in$controlling$severe$ operative$bleeding$in$pediatric$cardiac$surgery,$but$does$not$seem$to$increase$the$risk$of$thrombotic$complications$or$mortality$rate$in$ the$postoperative$period.$ $ $ 18.$Pei,$B.$B.,$et$al.$(2013).$"[Role$of$small"dose$recombinant$human$coagulation$factor$VIIa$for$coagulopathy$in$patients$with$isolated$ traumatic$brain$injury]."$Zhonghua$Yi$Xue$Za$Zhi$93(23):$1780"1783.$ $ OBJECTIVE:$To$explore$the$role$of$small"dose$recombinant$human$coagulation$factor$VIIa$(rFVIIa)$for$coagulopathy$in$patients$with$ isolated$traumatic$brain$injury.$METHODS:$A$total$of$86$isolated$traumatic$brain$patients$with$coagulopathy$were$treated$at$our$ neurosurgery$intensive$care$unit$(NICU)$from$January$2010$to$December$2012.$Their$trauma$registry$data$included$mortality,$pre"and$ post"rFVIIa$coagulation$parameters.$Two"tailed$paired$t"test$was$used$to$determine$significant$changes$in$coagulation$parameters$ and$other$major$clinical$parameters.$RESULTS:$Twenty"seven$patients$made$up$the$low"dose$rFVIIa$(20$microg/kg)$group.$And$the$ control$group$had$59$well"matched$subjects.$At$admission,$age,$blood$pressure,$Glasgow$coma$scale$score,$hemoglobin,$platelets$ and$international$normalize$ratio$were$similar$in$both$groups.$After$treatment,$the$INR$of$patients$on$rFVIIa$was$lower$than$that$of$the$ conventional$treatment$group$(1.1$+/"$0.2$vs$1.2$+/"$0.2,$P$<$0.01)$and$it$declined$more$in$the$rFVIIa$group$(0.3$+/"$0.2$vs$0.1$+/"$0.4,$ P$=$0.05).$No$significant$difference$existed$in$mortality$or$length$of$stay$between$two$groups.There$was$no$occurrence$of$subsequent$ thromboembolic$events.$CONCLUSION:$The$application$of$small"dose$rFVIIa$can$effectively$reduce$the$value$of$INR$and$improve$ the$coagulation$status$of$patients.$During$the$course$of$treatment,$no$major$adverse$events$occur.$ $ $ 20.$Scheffert,$J.$L.,$et$al.$(2013).$"Timing$of$factor$VIIa$in$liver$transplantation$impacts$cost$and$clinical$outcomes."$Pharmacotherapy$ 33(5):$483"488.$ $ STUDY$OBJECTIVE:$To$investigate$the$clinical$and$economic$outcomes$associated$with$the$use$of$recombinant$factor$VIIa$(rFVIIa)$ in$perioperative$liver$transplantation$(LT).$DESIGN:$Retrospective$review.$SETTING:$Academic$medical$center.$PATIENTS:$A$total$of$ 63$adults$who$underwent$LT$between$January$2000$and$September$2008$and$received$rFVIIa$prior$to$or$during$the$procedure.$Using$ a$propensity"scoring$method,$these$patients$were$matched$in$a$1:2$ratio$with$120$controls.$MEASUREMENTS$AND$MAIN$RESULTS:$ Of$the$473$patients$who$received$any$LT$during$the$study$period,$63$(13%)$received$rFVIIa$and$were$matched$with$propensity$score$ matched$controls$at$a$ratio$of$approximately$1:2.$Of$those$who$received$rFVIIa,$27$(43%)$received$preemptive$administration$and$14$ (22%)$received$intraoperative$administration.$(The$remaining$22$patients$received$rFVIIa$outside$of$a$12"hour$window$of$time$before$ or$after$surgery.)$Clinical$outcomes$were$similar$between$the$preemptive$and$the$control$groups,$although$patients$in$the$control$ D"21$ group$had$a$shorter$length$of$stay$in$the$intensive$care$unit$(ICU)$and$incurred$fewer$expenses.$Compared$with$both$the$preemptive$ and$the$control$groups,$patients$who$received$rFVIIa$intraoperatively$required$more$blood$products,$longer$stays$in$the$ICU,$and$ incurred$higher$costs.$They$also$had$poorer$graft$survival$and$decreased$overall$survival$rates$at$30$days$and$1$year.$ CONCLUSION:$Intraoperative$administration$of$rFVIIa$in$LT$was$associated$with$higher$blood$product$use,$lower$graft$and$patient$ survival$rates,$longer$ICU$stays,$and$higher$overall$costs$compared$with$preemptive$administration.$The$use$of$preemptive$rFVIIa$in$ select$high"risk$LT$patients$may$prevent$the$development$of$poor$clinical$outcomes$and$may$be$more$cost$effective$compared$with$ intraoperative$administration.$ $ $ 19.$Yuan,$Q.,$et$al.$(2015).$"Low"dose$recombinant$factor$VIIa$for$reversing$coagulopathy$in$patients$with$isolated$traumatic$brain$ injury."$J$Crit$Care$30(1):$116"120.$ $ PURPOSE:$The$purpose$of$this$study$was$to$investigate$the$role$of$low"dose$recombinant$factor$VIIa$(rFVIIa)$(20$mug/kg)$in$ reversing$coagulopathy$in$patients$with$isolated$traumatic$brain$injury$(TBI).$MATERIALS$AND$METHODS:$Patients$with$isolated$TBI$ and$coagulopathy$at$admission$were$enrolled$prospectively$from$January$2010$to$December$2011.$The$patients$were$divided$into$2$ groups:$the$rFVIIa$and$the$no"rFVIIa$groups.$In$the$rFVIIa$group,$patients$received$a$single$dose$of$20$mug/kg$rFVIIa$intravenously$ to$reverse$their$coagulopathy$in$addition$to$blood$products.$Patients$in$the$no"rFVIIa$group$received$only$blood$products$to$correct$ the$coagulopathy.$The$clinical$outcome$variables$evaluated$included$changes$in$coagulation$parameters$after$administration$for$ reversing$coagulopathy,$the$occurrence$of$progressive$hemorrhagic$injury$(PHI),$intensive$care$unit$length$of$stay,$the$incidence$of$ thromboembolic$complications,$inhospital$mortality,$and$90"day$Glasgow$Outcome$Scale.$RESULTS:$Eighty"seven$patients$were$ ultimately$included$in$this$study.$Of$them,$49$patients$were$treated$with$blood$products$alone,$whereas$38$patients$also$received$ rFVIIa$to$reverse$their$coagulopathy.$The$improvement$in$international$normalized$ratio$was$greater$in$the$rFVIIa$group$(0.26$[0.18" 0.39])$than$in$the$no"rFVIIa$group$(0.06$["0.11$to$0.30])$(P$=$.001).$In$addition,$the$improvement$in$lactate$was$also$greater$in$the$ rFVIIa$group$(0.33$["0.18$to$0.54])$than$in$the$no"rFVIIa$group$(0.04$["0.25$to$0.20])$(P$=$.029).$During$the$period$after$we$began$to$ correct$the$coagulopathy,$PHI$occurred$in$19$patients$(38.8%)$in$the$no"rFVIIa$group,$which$was$significantly$higher$than$that$in$the$ rFVIIa$group$(7,$18.4%K$P$=$.040).$The$rate$of$cerebral$infarction$was$similar$in$both$groups$(10.2%$vs$5.3%).$There$was$a$trend$ indicating$that$low"dose$rFVIIa$therapy$was$associated$with$a$lower$mortality,$but$the$association$was$not$statistically$significant$(P$=$ .266).$CONCLUSIONS:$The$use$of$low"dose$rFVIIa$(20$mug/kg)$is$effective$for$correcting$coagulopathy$in$patients$with$TBI$without$ an$increase$in$thromboembolic$events.$Moreover,$it$is$more$effective$for$preventing$the$occurrence$of$PHI.$ $ $ D"22$ ( Appendix(E.(Summary(Table( ( No$relevant$FDA$warnings$were$identified.$ ( Table$1.$Key$Question$1:$Indications,$Populations,$and$Characteristics$of$Comparative$Studies$of$Off"Label$rFVIIa$Use?$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)$ Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Indications(and(populations( Indications(and(populations( Indications(and(populations( Experts$did$not$ Conclusions$are$likely$ of(comparative(studies:( of(comparative(studies:( of(comparative(and(registry( comment$on$the$ current.$ Off"label$rFVIIa$use$was$ Indications$for$off"label$rFVIIa$ studies:( currency$of$this$ $ examined$in$24$RCTs$and$31$ use$were$consistent$in$the$ In$general,$we$identified$ conclusion.$One$ $ comparative$observational$ 2012$surveillance$report$as$in$ indications$for$off"label$rFVIIa$ expert$was$surprised$ studies$across$a$variety$of$ the$original$systematic$review.$ use$that$were$consistent$with$ there$were$no$ clinical$indications,$including$ Studies$examined$rFVIIa$use$ the$original$systematic$review:$ findings$from$the$ cardiac$surgery$(12$studies),$ for$intracranial$hemorrhage$ intracranial$hemorrhage$(one$ obstetric$literature,$ trauma$(nine$studies),$ (three$studies3,4,19),$body$ comparative$study5$and$one$ however$the$original$ intracranial$hemorrhage$(ICH)$ trauma$(eight$studies3,6<10,18,19),$ registry$study),2$body$trauma$ systematic$review$ (eight$studies),$liver$ traumatic$brain$injury$(one$ (one$comparative$study13),$ included$three$ transplantation$(eight$ study3)$and$those$undergoing$ traumatic$brain$injury$(two$ retrospective$ studies),prostatectomy$(one$ cardiac$surgery$(two$ comparative$studies15,17),$liver$ comparative$studies$ study),$other$liver$disease$(five$ studies3,12,20)$and$liver$ transplantation$(one$ on$rFVIIa$use$in$ studies),$ transplantation11.$$ comparative$study16),$adult$ obstetrics/gynecology$ obstetrics/gynecology$(three$ $ cardiac$surgery$(one$registry$ (see$the$first$column$ studies),$hematology/oncology$ Characteristics(of( study2),$$and$pediatric$cardiac$ for$details).$The$other$ (three$studies),$and$other$ comparative(studies:$ surgery$(one$comparative$ expert$suggested$a$ surgery$(six$studies).$There$ Consistent$with$the$original$ study14).$The$registry$study2$ registry$study2$$that$ were$prominent$community$ systematic$review,$the$2012$ also$examined$off"label$rFVIIa$ was$previously$ uses$that$lacked$studies,$such$ literature$search$identified$ use$for$other$surgery,$obstetric$ excluded$from$our$ as$primary$clotting$disorders$ both$RCTs4,8,9,18,21,$and$ hemorrhage,$and$ literature$analysis$that$ other$than$hemophilia,$ observational$ hematology/oncology.$$ we$decided$to$include$ secondary$clotting$disorders,$ studies6,7,10,12,19,20,22.$One$ $ (see$the$third$column$ and$gastrointestinal$bleeding$ systematic$review23$and$two$ Characteristics(of( for$details)$and$a$ not$related$to$liver$disease.$ meta E"1$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)$ Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! aneurysm,$other$vascular$ a$wide$range$of$ages$(24"76$ surveillance$report$were$ hemorrhage$that$was$ procedures,$and$neonatal$use$ years$old)$and$dosages$of$ observationalK$only$one$RCT5$ previously$excluded$ (beyond$cardiac$surgery).$ rFVIIa$(5"360$µg/kg$of$patient$ was$identified.$Sample$sizes$ from$our$analysis$ Many$studies$examined$only$ weight)$were$represented.$The$ ranged$from$a$minimum$of$n=$ because$it$examined$ prophylactic$use$of$rFVIIa$for$ sample$size$of$included$ 215$to$n=3,446$individuals.2$ human,$rather$than$ clinical$indications$where$ studies$ranged$from$16918$to$ Consistent$with$the$original$ recombinant,$FVIIa.$ treatment$or$end"stage$use$ 1,3973$among$RCTs$and$2412$ review,$studies$varied$in$the$ may$also$be$frequent.$ to$2,0506$in$observational$ dosage$of$rFVIIa$ Individuals$included$in$the$ studies,$which$is$consistent$ administered,$and$one$ comparative$studies$were$ with$the$range$found$in$the$ identified$study$compared$high$ generally$younger$and$had$ original$review.$$Also$ and$low$doses13.$Consistent$ lower$clinical$acuity$in$ consistent$with$the$original$ with$the$original$review,$most$ comparison$to$individuals$in$ systematic$review,$most$ studies$reported$direct$ community$practice.$$ studies$reported$direct$ outcomes,$such$as$ ( outcomes,$such$as$ mortality2,14"17,24$and$ Characteristics(of( thromboembolic$ thromboembolic$events$ comparative(studies:( events3,4,6,8,10,11,19,20,23$and$ (TEs).2,5,13,14,24$ With$the$exception$of$use$in$ mortality.6<8,10,11,18,21,23$ $ ICH,$study$sample$sizes$were$ Note:$Upon$further$ small$(median$of$24$treated$ consideration$of$the$limitations$ individuals).$Studies$of$ICH$ of$examining$only$comparative$ included$two$large$RCTs$of$ studies$for$the$purpose$of$ almost$900$individuals$treated$ describing$indications$of$off" with$rFVIIa.$Dosage$varied$ label$rFVIIa$use,$we$decided$ from$5$to$956$mcg/kg$of$ to$include$registry$studies$for$ patient$weight,$and$only$for$ this$question.$This$decision$ intracranial$hemorrhage$was$ occurred$after$sending$ there$a$sufficient$range$of$ literature$search$findings$to$ doses$to$assess$the$impact$of$ experts.$We$included$one$ rFVIIa$dosing$on$outcomes.$ additional$study$2$as$a$result$of$ Most$studies$used$indirect$ this$decision,$which$is$ endpoints$as$their$primary$ described$above.$$ outcomes,$particularly$red$ $$ blood$cell$(RBC)$transfusion$ requirements,$blood$loss,$and$ E"2$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)$ Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! duration$of$surgery$or$ Intensive$Care$Unit$(ICU)$stay.$ Direct$outcomes,$such$as$ mortality,$functional$status,$or$ thromboembolic$events,$were$ frequently$reported,$but$most$ studies$were$individually$ underpowered$to$evaluate$ them.$$ $ Note:$The$form$we$sent$to$ experts$included$a$list$of$the$ off"label$indications$that$ comprised$69%$of$all$identified$ comparative$studies$(cardiac$ surgery,$trauma,$intracranial$ hemorrhage,$liver$ transplantation,$and$ prostatectomy).$The$form$did$ not$include$a$list$of$the$ indications$that$comprised$the$ remaining$31%$of$comparative$ studies$(other$liver$disease,$ obstetrics/gynecology,$ hematology/oncology,$and$ other$surgery).$We$have$ added$these$additional$4$ indications$to$this$table$(see$ “indications$and$populations$of$ comparative$studies”$above)$ for$clarification$purposes.$$ Abbreviations:$ICH=Intracranial$HemorrhageK$ICU=Intensive$Care$UnitK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$ rFVIIa=Recombinant$Factor$Seven"AK$TE=Thromboembolic$Events$ E"3$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ ( Table$2.$Key$Question$2:$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Intracranial$Hemorrhage$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcome:(Mortality((90(day)( Assessment:(Current( No$studies$were$identified.$$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Moderate( An$expert$reviewer$suggested$ original$conclusion$ current.$ Four(RCTs,(one(comparative( an$article25$on$using$rFVIIa$to$ was$still$current,$and$ $ observational(study( treat$cerebral$hemorrhage$in$ the$other$did$not$ Meta"analysis$found$no$effect$ acute$promyelocytic$leukemia$ comment$on$ of$rFVIIa$on$mortality$(risk$ individuals,$but$it$did$not$meet$ currency.$$ difference:$low"dose$group:$ inclusion$criteria$(was$not$a$ 0.031$[95%$CI$"0.086$to$0.024],$ randomized$or$observational$ medium"dose$group:$0.020$ study).$ [95%$CI$"0.076$to$0.036],$high" dose$group:$0.027$[95%$CI$" 0.121$to$0.068]).$No$difference$ in$mortality$was$found$in$the$ observational$study.$ Outcome:(Arterial( Assessment:(Current*( No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ Thromboembolic(Events( Two$studies$examined$the$ original$conclusion$ current.$ (Arterial(TEs)( association$between$rFVIIa$ was$still$current,$and$ $ SOE:(Moderate( use$and$risk$of$arterial$ the$other$did$not$ Four(RCTs,(one(comparative( thromboembolic$events$ comment$on$ observational(study( (arterial$TEs).$$ currency.$$ Meta"analysis$found$ •$ One$RCT4$(n=841)$ significantly$higher$rates$of$ demonstrated$an$ arterial$thromboembolic$events$ association$between$higher$ with$medium$and$high$doses$of$ doses$of$rFVIIa$and$arterial$ rFVIIa$compared$to$usual$care,$ TEs$as$compared$to$no" and$a$similar,$but$non" rFVIIa$group$(odds$ significant,$finding$for$low$doses$ ratio=2.14K$p=0.031).$$ of$rFVIIa$(risk$difference:$low$ •$ A$meta E"4$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! [95%$CI$0.008$to$0.062],$high$ nervous$system$bleeding$ dose$0.063$[95%$CI$0.011$to$ individuals)3$found$a$similar$ 0.063]).$The$observational$ association$between$higher$ study$only$identified$one$TE,$in$ doses$of$rFVIIa$and$arterial$ the$rFVIIa$group.$ TEs$compared$to$no E"5$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Hematoma(volume( No$studies$were$identified.$ individuals$receiving$surgery$ original$conclusion$ current.$ SOE:(Moderate( for$spontaneous$ was$still$current,$and$ $ Four(RCTs( supratentorial$intracerebral$ the$other$did$not$ Meta"analysis$found$significant$ hemorrhage$compared$the$ comment$on$ reductions$in$relative$ use$of$rFVIIa$(100$mcg/KG$ currency.$ hematoma$expansion$in$the$ b.w.)$to$placebo$and$found$ rfVIIa$group$compared$to$usual$ similar$reductions$in$ care$at$all$dosing$levels$ intracerebral$hemorrhage$ (standardized$mean$difference:$ volumes$following$hematoma$ low$dose$"0.146$[95%$CI$"0.291$ evacuation$at$18"30$hours$ to$"0.001],$medium$dose$"0.240$ (mean$difference$2.1$mL,$ [95%$CI$"0.385$to$"0.095],$high$ 95%$confidence$interval$" dose$"0.334$[95%$CI$"0.579$to$" 12.1$to$16.2,$P=0.76$[0.03$ 0.090]).$$ mL$after$adjustment$for$ baseline$value]).$$ Abbreviations:$BW=By$WeightK$CI=Confidence$IntervalK$mRS=Modified$Rankin$ScaleK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$ Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ *$Indicates$the$assessment$of$currency$was$changed$from$“possibly$out$of$date”$to$“current”$in$the$current$review$due$to$the$removal$of$the$two$ meta"analyses3,11$whose$results$were$previously$included$in$the$original$systematic$review.$$ $ Table$3.$Key$Question$3a:$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Massive$Bleeding$from$Trauma$(Body$Trauma)$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcome:(Mortality((30(days)( Assessment:(Current*! No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Low( Three$RCTs$and$one$ original$conclusion$ current.$ Two(RCTs,(three(comparative( observational$study$examined$ was$still$current,$and$ $ observational(studies( mortality$rates$associated$with$ the$other$did$not$ Although$the$2012$ •$ Among$individuals$who$ rFVIIa$versus$no"rFVIIa$ comment$on$ surveillance$report$ survived$at$least$48$hours,$ groups.$$ currency.$ determined$that$an$ E"6$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! RCTs$note$no$difference$ •$ One$RCT$recommend$by$ RCT6$and$an$ between$rfVIIa$and$usual$ an$expert$reviewer8$ observational$study7$$ care$in$30"day$mortality.$ (n=560)$compared$rFVIIa$ conflict$with$the$ Evidence$from$ use$to$placebo$and$found$ original$conclusions,$it$ observational$studies$ no$significant$difference$in$ is$our$assessment$ weakly$favored$rFVIIa.$( 30"day$mortality$between$ that$the$conclusion$is$ Of$note,$studies$had$differing$ groups$(12.2%$vs$11.1%K$ likely$current.$$ exclusion$criteria$for$48"hour$ p=$0.61).$ mortality,$and$none$of$them$ •$ A$second$RCT6$(n=2,050)$ were$sufficiently$powered$to$ found$similar$mortality$ detect$differences$in$30"day$ rates$among$rFVIIa$and$ mortality.$ no"rFVIIa$groups$(20.0%$ vs$14.3%K$p>0.05).$ However,$this$study$also$ demonstrated$significantly$ increased$mortality$rate$ with$the$use$of$rFVIIa$in$ regression$analysis$(OR:$ 1.67,$95%$CI:$1.08$to$2.60K$ p=0.02).$$ •$ A$third$RCT9$(n=573)$ found$no$difference$in$30" day$mortality$between$ rFVIIa$and$no"rFVIIa$ groups$for$individuals$with$ blunt$trauma$(11.0%$ vs10.7%,$p=$0.93)$or$for$ individuals$with$ penetrating$trauma$(18.2%$ vs13.2%K$p=$0.40).$$ •$ A$retrospective$cohort$ study$recommended$by$an$ expert$reviewer7$found$no$ difference$in$mortality$for$ rFVIIa$compared$to$no" E"7$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! rFVIIa$in$terms$of$ transfusions$less$ than/equal$to$20$units$(24" hour:$25%$vs$24%K$30" day:$25%$vs$42%)$or$21$to$ 30$units$(24"hour:$33%$vs$ 47%,$30"day:$55%$vs$ 50%).$However,$for$initial$ requirement$of$more$ than/equal$to$30$units$of$ RBCs,$24"hour$mortality$ (26%$vs$64%,$P$=$0.02)$ was$significantly$ decreased$in$individuals$ that$received$rFVIIa$ compared$with$those$who$ did$not.$These$mortality$ differences$were$not$ maintained$at$30$days$ (68%$vs$71%).$$ Outcome:(Thromboembolic( Assessment:(Current! A$retrospective$cohort$ One$expert$felt$the$ Conclusions$are$likely$ Events((TEs)( Two$studies$found$no$ study13$(n=152)$of$individuals$ original$conclusion$ current.$ SOE:(Low( difference$between$rFVIIa$and$ receiving$off$label$rFVIIa$in$a$ was$still$current,$and$ $ Two(RCTs,(three(comparative( no"rFVIIa$groups$on$risk$of$ large$academic$center$ the$other$did$not$ observational(studies( TEs.$$ (2005"2012)$compared$rates$ comment$on$ •$ Studies$found$no$difference$ •$ A$meta E"8$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! difference$between$rFVIIa$ There$was$no$significant$ and$no"rFVIIa$groups$in$ difference$in$TE$by$dose.$$ risk$of$arterial$or$venous$ TEs.$$$ Outcome:(Units(of(RBCs( Assessment:(Current! No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ Transfused( A$RCT$and$two$observational$ original$conclusion$ current.$ SOE:(Low( studies$examined$units$of$ was$still$current,$and$ $ Two(RCTs,(one(comparative( RBCs$transfused$for$rFVIIa$vs$ the$other$did$not$ observational(studies( no"rFVIIa$groups$ comment$on$ •$ For$blunt$trauma$ •$ A$RCT9$(n=573)$found$that$ currency.$ individuals,$one$RCT$found$ blunt$trauma$individuals$ a$significant$reduction$in$ who$received$rFVIIa$used$ RBC$transfusions$for$rFVIIa$ significantly$fewer$RBC$ compared$to$no"rFVIIa.$ units$over$48$hours$ Another$RCT$among$ compared$to$no"rFVIIa$ penetrating$trauma$ group$(\(mean±SD)$7.8$±$ individuals$found$similar$but$ 10.6$versus$9.1±11.3K$p=$ non"significant$reductions$in$ 0.04).$However,$ RBC$transfusions.$The$ penetrating$trauma$ observational$study$found$ individuals$who$received$ an$increase$in$transfusion$ rFVIIa$had$non" requirements$associated$ significantly$reduced$RBC$ with$rFVIIa$compared$to$ units$over$48$hours$ usual$care.$$ compared$to$no"rFVIIa$ Of$note,$comparisons$across$ (5.0±7.4$versus$6.8$±$6.9K$ studies$are$difficult$due$to$ p=$0.11.7)$$ differing$exclusion$criteria$for$ •$ A$retrospective$cohort$ early$in"hospital$mortality.$$ study$7$(n=228)$ recommend$by$an$expert$ E"9$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! reviewer$examined$rFVIIa$ compared$to$no"rFVIIa$ among$massively$ transfused$individuals.$The$ study$found$reduced$RBC$ units$in$rFVIIa$compared$ to$no"rFVIIa$over$6$hours$ (mean:$35.6±2.6$vs.$ 25.6±0.7K$p=0.001)$and$24$ hours$(mean:$38.6±2.9$vs.$ 28.0±1.0K$p=0.00).$$ •$ Another$retrospective$ cohort$study6$found$no$ difference$between$those$ who$received$rFVIIa$and$ no"rFVIIa$in$the$number$ and$range$of$RBC$units$ used$(number(range)K$ rFVIIa:$10(6–16)$$vs$no" rFVIIa$10(4–17)K$p E"10$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! so$the$studies$were$likely$ underpowered$to$detect$any$ difference$between$groups.$ Abbreviations:$ARDS=Acute$Respiratory$Distress$SyndromeK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa" Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ $ Table$4.$Key$Question$3b.$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Massive$Bleeding$from$Trauma$(Brain$Trauma)$ i.e.,$Traumatic$Brain$Injury$[TBI])$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcome:(Mortality((15(days)(( Assessment:(Current$ Two$studies$found$no$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Low( A$retrospective$cohort$study$ difference$between$rFVIIa$and$ original$conclusion$ current.$ One(RCT,(one(comparative( 10$(n=28)$found$no$significant$ no"rFVIIa$groups$on$mortality.$$ was$still$current,$and$ $ observational(study( differences$between$rFVIIa$ •$ A$retrospective$cohort$ the$other$did$not$ •$ The$RCT$found$no$ and$no"rFVIIa$on$mortality$ study15$(n=86)$found$no$ comment$on$ difference$between$groups$ (50%$vs$29%K$p=0.22).$$ significant$difference$ currency.$ in$mortality$at$15$days,$with$ between$individuals$who$ rates$of$11%$in$each$group.$ received$low"dose$rFVIIa$ The$observational$study$ and$matched$no"rFVIIa$ found$a$reduced$mortality$ groups$on$mortality.$$ with$rFVIIa$compared$to$ •$ A$prospective$cohort$ usual$care$but$this$was$a$ study17$(n=87)$of$ non"significant$finding:$ individuals$with$TBI$and$ 33.3%$vs$52.9%$in$the$two$ coagulopathy$found$a$ groups,$respectively.$$ non"significant$reduction$ •$ The$findings$in$both$studies$ in$mortality$among$those$ are$limited$by$low$event$ who$received$low"dose$ rates.$$ rFVIIa$therapy$compared$ to$no"rFVIIa.$$ E"11$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcome:(Thromboembolic( Assessment:(Current$ A$retrospective$cohort$study15$ One$expert$felt$the$ Conclusions$are$likely$ events((TEs)((72(hours)(( Two$studies$assessed$the$ (n=86)$found$no$occurrence$of$ original$conclusion$ current.$ SOE:(Low( association$between$rFVIIa$ thromboembolic$events$in$ was$still$current,$and$ $ One(RCT,(one(comparative( and$TEs$as$compared$to$no" either$rFVIIa$or$matched$no" the$other$did$not$ observational(study( rFVIIa$groups.$$ rFVIIa$groups.$$ comment$on$ •$ The$RCT$found$TE$event$ •$ A$meta E"12$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcome:(RBC(Transfusion( Assessment:(Current*$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ Requirement( An$retrospective$study10$ original$conclusion$ current.$ No$studies$reported$on$this$ (n=28)$among$individuals$with$ was$still$current,$and$ $ outcome.$$$ TBI$undergoing$emergent$ the$other$did$not$ One$study18$identified$ craniotomy$found$a$significant$ comment$on$ in$the$2012$ reduction$of$RBC$units$in$ currency.$ surveillance$report$ individuals$receiving$rFVIIa$ found$a$reduction$in$ versus$no"rFVIIa$ RBC$units$among$ (median(range)$of$units:$ those$in$the$rFVIIa$ preoperative:$0$(0–2)$versus$4$ group$compared$to$ (2–8)K$p=$0.001K$$ no$rFVIIa,$while$the$ intraoperative:$1$(0–2)$versus$ original$review$found$ 5$(2–8)$K$p=0.002K$ no$evidence.$ postoperative:$1$(0–2)$versus$ However,$evidence$ 3$(2–5)K$p=$0.002K$and$total:$4$ remains$insufficient$to$ (1–5)$versus$14$(10–17)K$p=$ form$a$conclusion.$$ 0.001.)$ Outcome:(ICU(length(of(stay( No$studies$were$identified.$ A$retrospective$cohort$study15$ One$expert$felt$the$ Conclusions$are$likely$ No$studies$reported$on$this$ (n=86)$found$no$significant$ original$conclusion$ current.$ outcome.$$ difference$between$individuals$ was$still$current,$and$ $ who$received$low"dose$rFVIIa$ the$other$did$not$ One$study15$identified$ and$matched$no"rFVIIa$ comment$on$ in$the$2016$ individuals$on$length$of$ICU$ currency.$ surveillance$report$ stay.$ found$no$difference$ between$rFVIIa$and$ no"rFVIIa$groups$on$ length$of$ICU$stay.$ However,$evidence$ remains$insufficient$to$ form$a$conclusion.$ Abbreviations:$ICU=Intensive$Care$UnitK$RCB=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialsK$rFVIIa=Recombinant$Factor$Seven" AK$SD=Standard$DeviationK$SOE=Strength$of$EvidenceK$TBI=Traumatic$Brain$InjuryK$TE=Thomboembolic$EventK$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ E"13$ $ Table$5.$Key$Question$4a:$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Liver$Transplantation$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcomes:(Mortality( Assessment:(Current( An$retrospective$cohort$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Low( A$meta E"14$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! differences$in$TEs$between$ groups.$The$observational$ study$only$reported$one$ thromboembolic$event$"$ thrombosis$of$the$hepatic$ artery$in$a$patient$who$ received$rFVIIa.$$ Outcomes:(Units(of(RBCs( Assessment:(Current*$ An$retrospective$cohort$ One$expert$felt$the$ Conclusions$are$likely$ transfused(in(24Whour(postW A$meta E"15$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! minutes$less$in$the$rFVIIa$group$ compared$to$placebo.$None$of$ the$other$studies$identified$a$ significant$difference$between$ groups$ Outcomes:(ICU(length(of(stay( Assessment:(Current$$ An$retrospective$cohort$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Low( No$studies$were$identified.$ study16$(n=183)$compared$the$ original$conclusion$ current.$ Three(RCTs( use$of$rFVIIa$preemptively$or$ was$still$current,$and$ $ Three$RCTs$found$no$ intraoperatively$to$a$matched$ the$other$did$not$ An$observational$ difference$between$groups$in$ no"rFVIIa$group$and$found$ comment$on$ study16$found$that$ ICU$length$of$stay.$$ that$individuals$who$received$ currency.$ those$who$received$ $ rFVIIa$intraoperatively$had$ rFVIIa$intraoperatively$ longer$ICU$stays$than$those$ had$longer$ICU$stays$ receiving$rFVIIa$preemptively$ than$those$receiving$ or$the$no"rFVIIa$group.$ rFVIIa$preemptively$ and$the$no"rFVIIa$ group.$Intraoperative$ use$of$rFVIIa$was$not$ discussed$in$the$ original$systematic$ review.$$ Abbreviations:$CI=Confidence$IntervalK$ICU=Intensive$Care$UnitK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$ rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ *Indicates$the$assessment$of$currency$was$changed$from$“possibly$out$of$date”$to$“current”$in$the$current$review$due$to$the$removal$of$the$two$ meta"analyses3,11$whose$results$were$previously$included$in$the$original$systematic$review.$$ $ Table$6.$Key$Question$4b.i.$Use$of$rFVIIa$for$Selected$Indications$in$Individuals$With/Undergoing$Cardiac$Surgery$(Adult$Cardiac$Surgery)$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! E"16$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcomes:(Mortality((inW Assessment:(Current$$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ hospital)( No$studies$were$identified.$ original$conclusion$ current.$ SOE:(Low( was$still$current,$and$ $ Two(RCTs,(four(comparative( the$other$did$not$ observational(studies,(four( comment$on$currency.$ metaWanalyses( Meta"analysis$of$good"quality$ RCTs$and$observational$studies$ found$no$difference$in$mortality$ between$rFVIIa$and$usual$care$ (risk$difference$0.007K$95%$CI$" 0.049$to$0.063)$ Outcomes:(Thromboembolic( Assessment:(Current$$ No$studiewere$identified.$ One$expert$felt$the$ Conclusions$are$likely$ events( A$meta E"17$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! rFVIIa$groups,$respectively$(p$ values$0.11$and$<0.001).$One$ additional$observational$study$ found$no$difference$between$ groups,$and$another$found$a$ significant$effect$against$the$ rFVIIa$group$(i.e.,$increased$ transfusions$with$treatment).$ Outcomes:(ICU(length(of(stay( Assessment:(Current$$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Low( No$studies$were$identified.$$ original$conclusion$ current.$ One(RCT,(four(comparative( $ was$still$current,$and$ $ observational(studies( $ the$other$did$not$ One$RCT$found$no$significant$ comment$on$currency.$ difference$between$groups$in$ ICU$length$of$stay.$Findings$ among$observational$studies$ were$inconsistent:$one$cohort$ study$found$a$significantly$ longer$ICU$length$of$stay$for$ rFVIIa$individuals$but$two$others$ had$significant$and$non" significant$findings$in$the$ opposite$direction,$respectively.$ A$fourth$cohort$study$found$no$ difference$between$groups.$ Outcome:(Operating(room( Assessment:(Current( No$studies$were$identified.$$ One$expert$felt$the$ Conclusions$are$likely$ time( A$retrospective$chart$review12$ original$conclusion$ current.$ No$studies$reported$on$this$ (n=24)$recommended$by$an$ was$still$current,$and$ $ outcome.$ expert$reviewer$reported$ the$other$did$not$ lesser$median$operating$room$ comment$on$currency.$ time$for$rFVIIa$group$versus$ reoperation$for$refractory$ bleeding$after$surgery$group,$ however,$the$data$were$not$ reported.$ E"18$ Abbreviations:$CI=Confidence$IntervalK$ICU=Intensive$Care$UnitK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$ rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$EvidenceK$TE=Thromboembolic$Event$ Studies$in$italics=$the$prior$surveillance$assessment$identified$two$meta"analyses3,11K$however$upon$further$review,$we$discovered$that$all$studies$ included$in$these$meta"analysis,$for$these$indications,$appeared$in$the$original$systematic$review.$Thus,$we$are$not$considering$these$meta" analyses$in$the$determination$of$currency.$$ $ Table$7.Key$Question$4b.ii.$Use$of$rFVIIa$for$Selected$Indications$in$Patient$With/Undergoing$Cardiac$Surgery$(Pediatric$Cardiac$Surgery)$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcomes:(Mortality((inW Assessment:(Current$ A$retrospective$matched$ One$expert$felt$the$ Conclusions$are$likely$ hospital)( A$retrospective$matched$ case"control$study$14$(n=135)$ original$conclusion$ current.$ SOE:(Insufficient( case"control$study$20$(n=75)$ of$individuals$who$received$ was$still$current,$and$ $ No$studies$were$identified.$$ found$no$significant$ rFVIIa$(during$or$after$ the$other$did$not$ While$the$original$ $ difference$between$ cardiac$surgery)$and$ comment$on$currency.$ systematic$review$ individuals$receiving$rFVIIa$ matched$no"rFVIIa$group$ found$no$studies$ and$a$matched$no"rFVIIa$ found$no$significant$ examining$this$ group$on$mortality.$ differences$in$mortality$rates$ outcome,$the$2012$ (16%$vs$9.5%,$p=.208).$ and$2016$surveillance$ reports$each$identified$ a$retrospective$ matched$case"control$ study8,14$indicating$ there$are$no$ differences$between$ rFVIIa$and$no"rFVIIa$ in$mortality.$Evidence$ remains$insufficient.$$$ Outcomes:(Thromboembolic( Assessment:(Current$ A$retrospective$matched$ One$expert$felt$the$ Conclusions$are$likely$ events( A$retrospective$matched$ case"control$study$14$(n=135)$ original$conclusion$ current.$ SOE:(Insufficient( case"control$20$(n=75)$found$ of$individuals$who$received$ was$still$current,$and$ $ One(RCT( no$significant$differences$ rFVIIa$(during$or$after$ the$other$did$not$ While$the$original$ One$RCT$identified$no$ between$individuals$receiving$ cardiac$surgery)$and$ comment$on$currency.$ systematic$review$ thromboembolic$events$in$either$ rFVIIa$and$a$matched$no" matched$no"rFVIIa$group$ reported$insufficient$ rFVIIa$or$usual$care$groups.$$ rFVIIa$group$on$rate$of$TE$ found$no$significant$ evidence$for$this$ (8%$versus$4%K$p=NR).$$ differences$in$the$rate$of$ outcome,$the$2012$ thrombosis$(20%$vs$28%,$ and$2016$surveillance$ p=.540).$$ report$each$identified$ E"19$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! one$retrospective$ matched$case"control$ study8,14$indicating$ there$are$no$ differences$between$ rFVIIa$and$no"rFVIIa$ in$rates$of$TEs.$$$$ Outcomes:(Units(of(Whole( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ BIood/RBC(transfusion( A$retrospective$matched$ original$conclusion$ current.$ SOE:(Insufficient( case"control$20$(n=75)$found$ was$still$current,$and$ $ One(RCT( no$significant$differences$ the$other$did$not$ One$RCT$found$a$non" between$individuals$receiving$ comment$on$currency$ significant$decrease$in$ rFVIIa$and$a$matched$no" transfusion$requirements$for$ rFVIIa$group$on$RBC$ RBCs$and/or$whole$blood$in$the$ transfusion$requirements$ rFVIIa$group$compared$to$no" (93.2$mL/kg$versus$108.3$ rFVIIa$groups.$$ mL/kgK$p$=$0.225).$$ Outcomes:(Time(to(chest( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ closure( No$studies$were$identified.$ original$conclusion$ current.$ SOE:(Insufficient( was$still$current,$and$ $ One(RCT( the$other$did$not$ One$RCT$found$that$rFVIIa$ comment$on$currency$ individuals$had$a$longer$time$to$ chest$closure$than$did$no"rFVIIa$ groups$(98.8$minutes$(SE$27.3)$ versus$58.3$minutes$(SE$29.2),$ p=0.026).$$ Abbreviations:$NR=Not$ReportedK$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$Factor$Seven"AK$ SE=Standard$ErrorK$SOE=Strength$of$Evidence$ ( Table$8.$Key$Question$4c.$Use$of$rFVIIa$for$Selected$Indications$in$Patient$With/Undergoing$Prostatectomy$ E"20$ Conclusions(From(Original( Findings(and(Assessment( Literature(Analysis( Expert(Opinion( Surveillance( Systematic(Review((May( from(Most(Recent( (December(2015)( Assessment( 2010)(Link(to(report( Surveillance(Assessment( (February(2012)!Link(to( report! Outcomes:(Mortality((10(day)( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ SOE:(Insufficient( No$studies$were$identified.$ original$conclusion$ current.$ One(RCT( was$still$current,$and$ $ One$RCT$reported$no$deaths$in$ the$other$did$not$ either$rFVIIa$or$no"rFVIIa$ comment$on$the$ groups.$( currency.$$ Outcomes:(Thromboembolic( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ events( No$studies$were$identified.$ original$conclusion$ current.$ SOE:(Insufficient(( was$still$current,!but$ $ One(RCT( noted$that$ One$RCT$reported$a$single$TE$ prostatectomy$is$now$ (myocardial$infarction)$in$the$20$ associated$with$lower$ μg/kg$dose$of$rFVIIa$group.$( morbidity$due$to$the$ use$of$laparoscopic$ and$robotic$ technology.$The$other$ expert$did$not$ comment$on$currency.$$ Outcomes:(Units(of(RBCs( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ transfused( No$studies$were$identified.$ original$conclusion$ current.$ SOE:(Insufficient( was$still$current,$and$ $ One(RCT( the$other$did$not$ One$RCT$found$significantly$ comment$on$currency$ reduced$RBC$transfusion$ requirements$in$the$rFVIIa$ group$compared$to$usual$care.$( Outcomes:(Operative(Room( Assessment:(Current$ No$studies$were$identified.$ One$expert$felt$the$ Conclusions$are$likely$ time( No$studies$were$identified.$ original$conclusion$ current.$ SOE:(Insufficient( was$still$current,$and$ $ One(RCT( the$other$did$not$ One$RCT$found$significantly$ comment$on$currency$ reduced$operating$room$time$in$ the$rFVIIa$group$compared$to$ usual$care( E"21$ Abbreviations:$RBC=Packed$Red$Blood$CellsK$RCT=Randomized$Controlled$TrialK$rFVIIa=Recombinant$Factor$Seven"AK$SOE=Strength$of$ EvidenceK$TE=Thromboembolic$Event$ $ $ References( 1.$ Yank$V,$Tuohy$CV,$Logan$AC,$et$al.$AHRQ$Comparative$Effectiveness$Reviews.$Comparative$Effectiveness$of$In E"22$ 14.$ Martinez$Lopez$MC,$Alcaraz$Romero$AJ,$Martinez$Lopez$AB,$Fernandez"Llamazares$CM,$Ramos$Navarro$C.$[Risk$ assessment$of$thrombotic$events$after$the$use$of$activated$factor$VII].$Anales$de$pediatria$(Barcelona,$Spain$:$2003).$Sep$ 2013K79(3):177"181.$ 15.$ Pei$BB,$Li$CY,$Lu$X,$et$al.$[Role$of$small"dose$recombinant$human$coagulation$factor$VIIa$for$coagulopathy$in$patients$with$ isolated$traumatic$brain$injury].$Zhonghua$yi$xue$za$zhi.$Jun$18$2013K93(23):1780"1783.$ 16.$ Scheffert$JL,$Taber$DJ,$Pilch$NA,$McGillicuddy$JW,$Baliga$PK,$Chavin$KD.$Timing$of$factor$VIIa$in$liver$transplantation$ impacts$cost$and$clinical$outcomes.$Pharmacotherapy.$May$2013K33(5):483"488.$ 17.$ Yuan$Q,$Wu$X,$Du$ZY,$et$al.$Low"dose$recombinant$factor$VIIa$for$reversing$coagulopathy$in$patients$with$isolated$traumatic$ brain$injury.$Journal$of$critical$care.$Feb$2015K30(1):116"120.$ 18.$ McMullin$NR,$Wade$CE,$Holcomb$JB,$et$al.$Prolonged$prothrombin$time$after$recombinant$activated$factor$VII$therapy$in$ critically$bleeding$trauma$patients$is$associated$with$adverse$outcomes.$The$Journal$of$trauma.$Jul$2010K69(1):60"69.$ 19.$ Robinson$MT,$Rabinstein$AA,$Meschia$JF,$Freeman$WD.$Safety$of$recombinant$activated$factor$VII$in$patients$with$warfarin" associated$hemorrhages$of$the$central$nervous$system.$StrokeS$a$journal$of$cerebral$circulation.$Jul$2010K41(7):1459"1463.$ 20.$ Karsies$TJ,$Nicol$KK,$Galantowicz$ME,$Stephens$JA,$Kerlin$BA.$Thrombotic$risk$of$recombinant$factor$seven$in$pediatric$ cardiac$surgery:$a$single$institution$experience.$The$Annals$of$thoracic$surgery.$Feb$2010K89(2):570"576.$ 21.$ Christensen$MC,$Parr$M,$Tortella$BJ,$et$al.$Global$differences$in$causes,$management,$and$survival$after$severe$trauma:$the$ recombinant$activated$factor$VII$phase$3$trauma$trial.$The$Journal$of$trauma.$Aug$2010K69(2):344"352.$ 22.$ Witmer$CM,$Huang$YS,$Lynch$K,$Raffini$LJ,$Shah$SS.$Off"label$recombinant$factor$VIIa$use$and$thrombosis$in$children:$a$ multi"center$cohort$study.$The$Journal$of$pediatrics.$May$2011K158(5):820"825$e821.$ 23.$ Stanworth$SJ,$Birchall$J,$Doree$CJ,$Hyde$C.$Recombinant$factor$VIIa$for$the$prevention$and$treatment$of$bleeding$in$patients$ without$haemophilia.$The$Cochrane$database$of$systematic$reviews.$2007(2):CD005011.$ 24.$ McQuilten$ZK,$Crighton$G,$Engelbrecht$S,$et$al.$Transfusion$interventions$in$critical$bleeding$requiring$massive$transfusion:$a$ systematic$review.$Transfusion$medicine$reviews.$Apr$2015K29(2):127"137.$ 25.$ Nosari$A,$Caimi$TM,$Zilioli$V,$Molteni$A,$Mancini$V,$Morra$E.$Cerebral$hemorrhage$treated$with$NovoSeven$in$acute$ promyelocytic$leukemia.$Leukemia$&$lymphoma.$Jan$2012K53(1):160"161.$ 26.$ Lavigne"Lissalde$G,$Aya$AG,$Mercier$FJ,$et$al.$Recombinant$human$FVIIa$for$reducing$the$need$for$invasive$second"line$ therapies$in$severe$refractory$postpartum$hemorrhage:$a$multicenter,$randomized,$open$controlled$trial.$Journal$of$thrombosis$ and$haemostasis$:$JTH.$Apr$2015K13(4):520"529.$ E"23$